Gene expression profiling of colon cancer with DNA arrays

Abstract

Differential gene expression associated with histopathologic features of colorectal disease can be performed with nucleic acid arrays. Such arrays can comprise a pool of polynucleotide sequences from colon tissues, and the detection of the overexpression or underexpression of polynucleotide sequences (or subsequences or complements thereof) from this pool can provide information relating to the detection, diagnosis, stage, classification, monitoring, prediction, prevention or treatment of colorectal disease.

Description

SEQUENCE LISTING

The instant application contains a “lengthy” Sequence Listing which has been submitted via CD-R in lieu of a printed paper copy, and is hereby incorporated by reference in its entirety. Said CD-R, recorded on May 5, 2005, are labeled CRF, “Copy 1” and “Copy 2”, respectively, and each contains only one identical 3.63 Mb file NAMED 1423R03.APP.

FIELD OF THE INVENTION

The present invention relates to polynucleotide analysis and, in particular, to polynucleotide expression profiling of colorectal carcinomas using arrays of polynucleotides.

BACKGROUND

Colorectal carcinoma (CRC) is a frequent and deadly disease. Different groups of tumors have been defined according to aggressiveness, anatomical localization and putative genetic instability based on conventional histopathological and immunohistopathological analysis. However, these aforementioned diagnostic tools are not sufficient to accurately diagnose and predict survival. Gene expression microarrays improve these classifications and bring new insights on the underlying molecular mechanisms involved throughout colorectal tumorigenic progression.

Despite global scientific efforts to effectively treat colon cancer, little progress has been made during the last decade and colorectal cancer (CRC) remains one of the most frequent and deadly neoplasias in western countries. Current prognostic models based on histoclinical parameters inadequately describe the heterogeneity of CRC, and are not sufficient to predict prognosis and guide clinical treatment in the individual patients. Tumors with different genetic alteration with similar clinical presentation follow different evolutions. One goal of molecular analysis is to identify, among complex networks of genes involved in tumorigenic progression, markers that could differentiate subgroups of tumors with prognosis, hence providing physicians with a clinically useful diagnostic tool to treat individual patients based on molecular gene sets as previously described.

Previous studies have been largely focused on individual candidate genes of disease, contrasting with the molecular complexity of cancer. The multi-step progression of CRC is accompanied by a number of genetic alterations [KRAS, APC, P53 and mismatch repair (MMR) genes, WNT and TGF-alpha pathways] that accumulate and interact in heterogenous complex ways to exert their tumor promoting effects (Vogelstein, 1988; Fearon, 1990). Despite the large number of published studies, the clinical utility of these disparate observations and reports remain limited for CRC patients. For example, little is known about molecular alterations associated with the prognostic heterogeneity of disease or the microsatellite instability (MSI) phenotype, and no single molecular marker has been validated to accurately predict prognososis in clinical practice. New models based on a precise molecular understanding of disease are required to improve screening, diagnosis,treatment, and ultimately survival of patients.

DNA microarray technology allows the measure of the mRNA expression level of thousands of genes simultaneously in a single assay, thus providing a molecular definition of a sample adapted to address the combinatory and complex nature of cancers (Bertucci, 2001; Ramaswamy, 2002; Mohr, 2002). Gene expression profiling may reveal biologically and/or clinically relevant subgroups of tumors (Alizadeh, 2000; Garber, 2001; Kihara, 2001; Beer, 2002; Bertucci, 2002; Devilard, 2002; Singh, 2002) and significantly improve current mechanistic understanding of oncogenesis.

Gene expression profiling-based studies of CRC have so far compared normal to tumor tissue samples, or described the molecular heterogeniety in different stages of colorectal disease (Alon, 1999; Notterman, 2001; Lin, 2002; Backert, 1999; Zou, 2002; Agrawal, 2002; Kitahara, 2001; Williams, 2003; Tureci, 2003; Birkenkamp-Demtroder, 2002; Frederiksen, 2003), but none have directly addressed the issue of prognosis or MSI phenotype.

SUMMARY OF THE INVENTION

DNA microarrays may be utilized to elucidate discrete gene sets to improve the prognostic classification of CRC, identify novel potential therapeutic targets of carcinogenesis, describe new diagnostic and/or prognostic markers, and guide physician decisions on appropriate patient care.

The invention thus provides a method for analyzing differential gene expression associated with histopathologic features of colorectal disease, comprising the detection of the overexpression or underexpression of a pool of polynucleotide sequences in colon tissues, said pool comprising all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets I through 644 set forth in Table 1.

The invention further provides a method or prognosis or diagnosis of colon cancer, or for monitoring the treatment of a subject with a colon cancer. This method comprises the steps of 1) obtaining colon tissue nucleic acids from a patient; and 2) detecting the overexpression or underexpression of a pool of polynucleotide sequences in colon tissues. The pool of polynuclestide sequences comprises all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequnce sets 1 through 644, as set forth in Table 1.

The invention further provides a polynucleotide library, comprising a pool of polynucleotide sequences either overexpressed or underexpressed in colon tissue, said pool corresponding to all or part of the polynucleotide sequences of SEQ ID Nos. 1 through 1596.

The invention still further provides a method of detecting differential gene expression, comprises 1) obtaining a polynucleotide sample from a subject; 2) reacting said polynucleotide sample obtained in step (1) with a polynucleotide library of the invention; and 3) detecting the reaction product of step (2).

The invention still further provides a method of assigning a therapeutic regimen to subject with histopathological features of colorectal disease, comprising 1) classifying the subject as having a “poor prognosis” or a “good prognosis” on the basis of the method of differential gene expression analysis according to the invention, and 2) assigning the subject a therapeutic regimen. The therapeutic regimen will either (i) comprise no adjuvant chemotherapy if the subject is lymph node negative and is classified as having a good prognosis, or (ii) comprise chemotherapy if said patient has any other combination of lymph node status and expression profile.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1C show global gene expression profiles in colorectal cancer and non-cancerous samples.

FIGS. 2A-2B show hierarchical classifications of tissue samples using genes which discriminate between normal and cancer samples.

FIGS. 3A-3C show hierarchical classifications of CRC tissue samples using genes that discriminate metastatic from non-metastatic samples, correlated with survival.

FIGS. 4A-4C show hierarchical classifications of CRC tissue samples using discriminator genes selected by supervised analyses based on lymph node status, MSI phenotype and location of tumors.

FIGS. 5A-5C show the analysis of NM23 protein expression in colorectal tissue samples using tissue microarrays.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to DNA array, technology which can be used to analyse the expression of numerous (e.g., ˜8,000) genes in cancerous and non-cancerous colon tissue or cell samples. Unsupervised hierarchical clustering can be used to identify putative gene expression patterns that are precisely correlated to subgroups of tumors; and these sub-groups are notably correlated to patient prognosis, disease aggressiveness, and survival. Supervised analysis can be used to identify several genes differentially expressed between normal and cancer samples, and delineated subgroups of colon cancer can be defined by histoclinical parameters, including clinical outcome (i.e., 5-year survival of 100% in a group and 40% in the other group, p<0.005), lymph node invasion, tumors from the right or left colon, and MSI phenotype. Discriminator genes are associated with various cellular processes. The most significant discriminatory genes and/or potential markers identified by the present invention were further validated at the protein level using immunohistochemistry (IHC) on sections of tissue microarrays (TMA) on 190 tumor and normal samples (see Examples below).

The invention thus provides a method for analyzing differential gene expression associated with histopathologic features of colorectal disease, e.g., colon tumors, in particular colon cancer. The method of the invention comprises the detection of the overexpression or underexpression of a pool of polynucleotide sequences in colon tissues. The pool of polynucleotide sequences corresponds to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequences sets set forth in Table 1 below.

TABLE 1
Gene	Set
symbol	No.	Image	Name	Seq3′	Seq5′	Ref
CAPG	1	1012666	capping protein (actin filament),	SEQ ID No: 1		SEQ ID No: 2
			gelsolin-like
DEK	2	1016390	dek oncogene (dna binding)	SEQ ID No: 3		SEQ ID No: 4
DVL1	3	1030065	dishevelled, dsh homolog 1 (drosophila)	SEQ ID No: 5		SEQ ID No: 6
NOV	4	1046837	nephroblastoma overexpressed gene	SEQ ID No: 7		SEQ ID No: 8
CD79A	5	1056782	cd79a antigen (immunoglobulin-	SEQ ID No: 9		SEQ ID No: 10
			associated alpha)
MGC27076	6	108249	hypothetical protein mgc27076	SEQ ID No: 11	SEQ ID No: 12	SEQ ID No: 13
	7	108274		SEQ ID No: 14
	8	108292		SEQ ID No: 15
C1ORF28	9	108305	chromosome 1 open reading frame 28	SEQ ID No: 16	SEQ ID No: 17	SEQ ID No: 18
MAP2K2	10	108370	mitogen-activated protein kinase kinase 2	SEQ ID No: 19	SEQ ID No: 20	SEQ ID No: 21
LOC220115	11	108374	hypothetical protein loc220115		SEQ ID No: 22
	12	108399		SEQ ID No: 23
HRB	13	108490	hiv-1 rev binding protein	SEQ ID No: 24		SEQ ID No: 25
	14	110385	hypothetical gene supported by	SEQ ID No: 26	SEQ ID No: 27
			ak026041
LOC92906	15	110486	hypothetical protein bc008217	SEQ ID No: 28	SEQ ID No: 29	SEQ ID No: 30
SOX4	16	111461	sry (sex determining region y)-box 4	SEQ ID No: 31	SEQ ID No: 32	SEQ ID No: 33
GSTA2	17	113932	glutathione s-transferase a2	SEQ ID No: 34	SEQ ID No: 35	SEQ ID No: 36
MLLT3	18	1144752	myeloid/lymphoid or mixed-lineage	SEQ ID No: 37		SEQ ID No: 38
			leukemia (trithorax homolog,
			drosophila); translocated to, 3
TCF3	19	114639	transcription factor 3 (e2a	SEQ ID No: 39	SEQ ID No: 40	SEQ ID No: 41
			immunoglobulin enhancer binding
			factors e12/e47)
PMS2	20	116906	pms2 postmeiotic segregation increased	SEQ ID No: 42	SEQ ID No: 43	SEQ ID No: 44
			2 (s. cerevisiae)
LPP	21	117240	lim domain containing preferred	SEQ ID No: 45	SEQ ID No: 46	SEQ ID No: 47
			translocation partner in lipoma
PTPRC	22	117755	protein tyrosine phosphatase, receptor	SEQ ID No: 48		SEQ ID No: 49
			type, c
	23	117811	similar to [human ig rearranged gamma	SEQ ID No: 50	SEQ ID No: 51
			chain mrna, v-j-c region and complete
			cds.], gene product
C6ORF53	24	1184178	chromosome 6 open reading frame 53	SEQ ID No: 52		SEQ ID No: 53
PDPK1	25	1185650	3-phosphoinositide dependent protein	SEQ ID No: 54		SEQ ID No: 55
			kinase-1
	26	118634	similar to [human ig rearranged gamma	SEQ ID No: 56	SEQ ID No: 57
			chain mrna, v-j-c region and complete
			cds.], gene product
KCNJ15	27	119530	potassium inwardly-rectifying channel,	SEQ ID No: 58	SEQ ID No: 59	SEQ ID No: 60
			subfamily j, member 15
	28	119772	loc284066	SEQ IDNo: 61
USP9X	29	120009	ubiquitin specific protease 9, x	SEQ ID No: 62	SEQ ID No: 63	SEQ ID No: 64
			chromosome (fat facets-like drosophila)
HELZ	30	120572	helicase with zinc finger domain	SEQ ID No: 65		SEQ ID No: 66
ADD1	31	120783	adducin 1 (alpha)	SEQ ID No: 67		SEQ ID No: 68
ATP5L	32	121076	atp synthase, h+ transporting,	SEQ ID No: 69		SEQ ID No: 70
			mitochondrial f0 complex, subunit g
IFNAR1	33	121265	interferon (alpha, beta and omega)	SEQ ID No: 71	SEQ ID No: 72	SEQ ID No: 73
			receptor 1
ELAVL1	34	121366	elav (embryonic lethal, abnormal	SEQ ID No: 74		SEQ ID No: 75
			vision, drosophila)-like 1 (hu antigen r)
	35	122004	loc143724	SEQ ID No: 76
DSG1	36	122743	desmoglein 1	SEQ ID No: 77	SEQ ID No: 78	SEQ ID No: 79
OLFM1	37	122756	olfactomedin 1	SEQ ID No: 80		SEQ ID No: 81
C3	38	123379	complement component 3	SEQ ID No: 82		SEQ ID No: 83
C4BPA	39	123664	complement component 4 binding	SEQ ID No: 84	SEQ ID No: 85	SEQ ID No: 86
			protein, alpha
DMPK	40	123916	dystrophia myotonica-protein kinase	SEQ ID No: 87	SEQ ID No: 88	SEQ ID No: 89
RPL6	41	123948	ribosomal protein 16	SEQ ID No: 90	SEQ ID No: 91	SEQ ID No: 92
HLA-DQB1	42	123953	major histocompatibility complex, class	SEQ ID No: 93	SEQ ID No: 94	SEQ ID No: 95
			ii, dq beta 1
CENPF	43	124345	centromere protein f, 350/400 ka	SEQ ID No: 96	SEQ ID No: 97	SEQ ID No: 98
			(mitosin)
CSF1	44	124554	colony stimulating factor 1	SEQ ID No: 99		SEQ ID No: 100
			(macrophage)
NDST3	45	125806	n-deacetylase/n-sulfotransferase	SEQ ID No: 101	SEQ ID No: 102	SEQ ID No: 103
			(heparan glucosaminyl) 3
SPI1	46	127394	spleen focus forming virus (sffv)	SEQ ID No: 104	SEQ ID No: 105	SEQ ID No: 106
			proviral integration oncogene spi1
ATP5C1	47	127950	atp synthase, h+ transporting,	SEQ ID No: 107	SEQ ID No: 108	SEQ ID No: 109
			mitochondrial f1 complex, gamma
			polypeptide 1
TNFSF10	48	128413	tumor necrosis factor (ligand)	SEQ ID No: 110	SEQ ID No: 111	SEQ ID No: 112
			superfamily, member 10
ASBABP2	49	129112	aspecific bcl2 are-binding protein 2	SEQ ID No: 113		SEQ ID No: 114
COX7A2L	50	129146	cytochrome c oxidase subunit viia	SEQ ID No: 115	SEQ ID No: 116	SEQ ID No: 117
			polypeptide 2 like
XTP5	51	129227	minor histocompatibility antigen ha-8	SEQ ID No: 118	SEQ ID No: 119	SEQ ID No: 120
GATA3	52	129757	gata binding protein 3	SEQ ID No: 121		SEQ ID No: 122
STK6	53	129865	serine/threonine kinase 6	SEQ ID No: 123		SEQ ID No: 124
FLJ14297	54	130173	hypothetical protein flj14297	SEQ ID No: 125	SEQ ID No: 126	SEQ ID No: 127
HEYL	55	132307	hairy/enhancer-of-split related with	SEQ ID No: 128	SEQ ID No: 129	SEQ ID No: 130
			yrpw motif-like
CD2	56	1326652	cd2 antigen (p50), sheep red blood cell	SEQ ID No: 131		SEQ ID No: 132
			receptor
GRF2	57	133334	guanine nucleotide-releasing factor 2	SEQ ID No: 133		SEQ ID No: 134
			(specific for crk proto-oncogene)
ITGAL	58	1338831	integrin, alpha 1 (antigen cd11a (p180),	SEQ ID No: 135		SEQ ID No: 136
			lymphocyte function-associated antigen
			1; alpha polypeptide)
SPIB	59	1350545	spi-b transcription factor (spi-1/pu.1	SEQ ID No: 137		SEQ ID No: 138
			related)
S100P	60	135221	s100 calcium binding protein p	SEQ ID No: 139	SEQ ID No: 140	SEQ ID No: 141
PVRL3	61	135302	poliovirus receptor-related 3	SEQ ID No: 142	SEQ ID No: 143	SEQ ID No: 144
	62	136361		SEQ ID No: 145	SEQ ID No: 146
COX6A1	63	139069	cytochrome c oxidase subunit via	SEQ ID No: 147	SEQ ID No: 148	SEQ ID No: 149
			polypeptide 1
IL2RB	64	139073	interleukin 2 receptor, beta	SEQ ID No: 150	SEQ ID No: 151	SEQ ID No: 152
CDK2	65	1391584	cyclin-dependent kinase 2	SEQ ID No: 153		SEQ ID No: 154
GPR1	66	139304	g protein-coupled receptor 1	SEQ ID No: 155	SEQ ID No: 156	SEQ ID No: 157
PSG6	67	139392	pregnancy specific beta-1-glycoprotein 6	SEQ ID No: 158	SEQ ID No: 159	SEQ ID No: 160
EPS15	68	139789	epidermal growth factor receptor	SEQ ID No: 161	SEQ ID No: 162	SEQ ID No: 163
			pathway substrate 15
APRT	69	141998	adenine phosphoribosyltransferase	SEQ ID No: 164	SEQ ID No: 165	SEQ ID No: 166
TGFB1I1	70	1423050	transforming growth factor beta 1	SEQ ID No: 167		SEQ ID No: 168
			induced transcript 1
FKBP2	71	143519	fk506 binding protein 2, 13 kda	SEQ ID No: 169	SEQ ID No: 170	SEQ ID No: 171
	72	144853		SEQ ID No: 172
BLVRA	73	145269	biliverdin reductase a	SEQ ID No: 173	SEQ ID No: 174	SEQ ID No: 175
SLC30A5	74	145286	solute carrier family 30 (zinc	SEQ ID No: 176	SEQ ID No: 177	SEQ ID No: 178
			transporter), member 5
AZGP1	75	1456160	alpha-2-glycoprotein 1, zinc	SEQ ID No: 179		SEQ ID No: 180
	76	1456315	homo sapiens cdna flj30452 fis, clone	SEQ ID No: 181
			brace2009293.
KLRD1	77	145696	killer cell lectin-like receptor subfamily		SEQ ID No: 182	SEQ ID No: 183
			d, member 1
FOLR2	78	146494	folate receptor 2 (fetal)	SEQ ID No: 184	SEQ ID No: 185	SEQ ID No: 186
	79	146922		SEQ ID No: 187	SEQ ID No: 188
PTGS2	80	147050	prostaglandin-endoperoxide synthase 2	SEQ ID No: 189	SEQ ID No: 190	SEQ ID No: 191
			(prostaglandin g/h synthase and
			cyclooxygenase)
PECAM1	81	147341	platelet/endothelial cell adhesion	SEQ ID No: 192		SEQ ID No: 193
			molecule (cd31 antigen)
PSEN1	82	147495	presenilin 1 (alzheimer disease 3)	SEQ ID No: 194	SEQ ID No: 195	SEQ ID No: 196
	83	1493187	homo sapiens, clone image: 4831215,	SEQ ID No: 197
			mrna
GATA2	84	149809	gata binding protein 2	SEQ ID No: 198	SEQ ID No: 199	SEQ ID No: 200
CHST13	85	1500894	carbohydrate (chondroitin 4)	SEQ ID No: 201		SEQ ID No: 202
			sulfotransferase 13
IGF1R	86	150361	insulin-like growth factor 1 receptor	SEQ ID No: 203	SEQ ID No: 204	SEQ ID No: 205
SOCS2	87	150644	suppressor of cytokine signaling 2	SEQ ID No: 206	SEQ ID No: 207	SEQ ID No: 208
INSR	88	151149	insulin receptor		SEQ ID No: 209	SEQ ID No: 210
TFDP1	89	151495	transcription factor dp-1	SEQ ID No: 211	SEQ ID No: 212	SEQ ID No: 213
IL10RA	90	151740	interleukin 10 receptor, alpha	SEQ ID No: 214	SEQ ID No: 215	SEQ ID No: 216
LYK5	91	152467	protein kinase lyk5	SEQ ID No: 217	SEQ ID No: 218	SEQ ID No: 219
MYBL1	92	1526789	v-myb myeloblastosis viral oncogene	SEQ ID No: 220
			homolog (avian)-like 1
LIF	93	153025	leukemia inhibitory factor (cholinergic	SEQ ID No: 221	SEQ ID No: 222	SEQ ID No: 223
			differentiation factor)
EIF4G3	94	153141	eukaryotic translation initiation factor 4	SEQ ID No: 224	SEQ ID No: 225	SEQ ID No: 226
			gamma, 3
TGFB1I1	95	153461	transforming growth factor beta 1	SEQ ID No: 227	SEQ ID No: 228	SEQ ID No: 168
			induced transcript 1
TJP3	96	153474	tight junction protein 3 (zona occludens	SEQ ID No: 229	SEQ ID No: 230	SEQ ID No: 231
			3)
STC1	97	153589	stanniocalcin 1	SEQ ID No: 232	SEQ ID No: 233	SEQ ID No: 234
DES	98	153854	desmin	SEQ ID No: 235	SEQ ID No: 236	SEQ ID No: 237
FCGBP	99	154172	fc fragment of igg binding protein	SEQ ID No: 238		SEQ ID No: 239
PMSCL2	100	154335	polymyositis/scleroderma autoantigen	SEQ ID No: 240	SEQ ID No: 241	SEQ ID No: 242
			2, 100 kda
PLCD1	101	154600	phospholipase c, delta 1	SEQ ID No: 243	SEQ ID No: 244	SEQ ID No: 245
CRIP1	102	155219	cysteine-rich protein 1 (intestinal)	SEQ ID No: 246		SEQ ID No: 247
BCKDK	103	155774	branched chain alpha-ketoacid	SEQ ID No: 248	SEQ ID No: 249	SEQ ID No: 250
			dehydrogenase kinase
TCF3	104	156505	transcription factor 3 (e2a	SEQ ID No: 251		SEQ ID No: 41
			immunoglobulin enhancer binding
			factors e12/e47)
ZNF463	105	156718	zinc finger protein 463	SEQ ID No: 252		SEQ ID No: 253
MCP	106	158233	membrane cofactor protein (cd46,	SEQ ID No: 254	SEQ ID No: 255	SEQ ID No: 256
			trophoblast-lymphocyte cross-reactive
			antigen)
LTBP4	107	158239	latent transforming growth factor beta	SEQ ID No: 257	SEQ ID No: 258	SEQ ID No: 259
			binding protein 4
MEIS1	108	1591384	meis1, myeloid ecotropic viral	SEQ ID No: 260		SEQ ID No: 261
			integration site 1 homolog (mouse)
ACE	109	159885	angiotensin i converting enzyme	SEQ ID No: 262		SEQ ID No: 263
			(peptidyl-dipeptidase a) 1
CD3E	110	159903	cd3e antigen, epsilon polypeptide (tit3	SEQ ID No: 264		SEQ ID No: 265
			complex)
MGC39325	111	165818	hypothetical protein mgc39325	SEQ ID No: 266	SEQ ID No: 267	SEQ ID No: 268
PRKACA	112	166052	protein kinase, camp-dependent,		SEQ ID No: 269	SEQ ID No: 270
			catalytic, alpha
SERPINB5	113	1662274	serine (or cysteine) proteinase inhibitor,	SEQ ID No: 271		SEQ ID No: 272
			clade b (ovalbumin), member 5
HSF4	114	1667886	heat shock transcription factor 4	SEQ ID No: 273		SEQ ID No: 274
DOK2	115	1671188	docking protein 2, 56 kda	SEQ ID No: 275		SEQ ID No: 276
EEF1A1	116	1683100	eukaryotic translation elongation factor	SEQ ID No: 277		SEQ ID No: 278
			1 alpha 1
S100A12	117	1705397	s100 calcium binding protein a12	SEQ ID No: 279		SEQ ID No: 280
			(calgranulin c)
CAMK2B	118	172444	calcium/calmodulin-dependent protein	SEQ ID No: 281	SEQ ID No: 282	SEQ ID No: 283
			kinase (cam kinase) ii beta
PLCG2	119	1731982	phospholipase c, gamma 2	SEQ ID No: 284		SEQ ID No: 285
			(phosphatidylinositol-specific)
NME1	120	174388	non-metastatic cells 1, protein (nm23a)	SEQ ID No: 286	SEQ ID No: 287	SEQ ID No: 288
			expressed in
PTGDS	121	178305	prostaglandin d2 synthase 21 kda (brain)	SEQ ID No: 289	SEQ ID No: 290	SEQ ID No: 291
PP	122	179232	pyrophosphatase (inorganic)	SEQ ID No: 292		SEQ ID No: 293
PPP2R2C	123	179264	protein phosphatase 2 (formerly 2a),	SEQ ID No: 294
			regulatory subunit b (pr 52), gamma
			isoform
	124	179776		SEQ ID No: 295
	125	181827		SEQ ID No: 296
TP53	126	1847162	tumor protein p53 (li-fraumeni	SEQ ID No: 297		SEQ ID No: 298
			syndrome)
DARS	127	186331	aspartyl-trna synthetase	SEQ ID No: 299	SEQ ID No: 300	SEQ ID No: 301
EGF	128	1869652	epidermal growth factor (beta-	SEQ ID No: 302		SEQ ID No: 303
			urogastrone)
RPL29P2	129	190103	ribosomal protein 129 pseudogene 2	SEQ ID No: 304	SEQ ID No: 305
EEF1B2	130	1902297	eukaryotic translation elongation factor	SEQ ID No: 306		SEQ ID No: 307
			1 beta 2
STK6	131	1912132	serine/threonine kinase 6	SEQ ID No: 308		SEQ ID No: 124
TAL1	132	191548	t-cell acute lymphocytic leukemia 1	SEQ ID No: 309
RPS15A	133	191714	ribosomal protein s15a	SEQ ID No: 310		SEQ ID No: 311
RPS19	134	192242	ribosomal protein s19	SEQ ID No: 312		SEQ ID No: 313
HRD1	135	192515	hrd1 protein	SEQ ID No: 314		SEQ ID No: 315
PTPN21	136	192581	protein tyrosine phosphatase, non-	SEQ ID No: 316		SEQ ID No: 317
			receptor type 21
NDUFA4	137	193672	nadh dehydrogenase (ubiquinone) 1	SEQ ID No: 318	SEQ ID No: 319	SEQ ID No: 320
			alpha subcomplex, 4, 9 kda
TSG101	138	194350	tumor susceptibility gene 101	SEQ ID No: 321	SEQ ID No: 322	SEQ ID No: 323
SDHD	139	195013	succinate dehydrogenase complex,	SEQ ID No: 324	SEQ ID No: 325	SEQ ID No: 326
			subunit d, integral membrane protein
DAP3	140	195702	death associated protein 3	SEQ ID No: 327	SEQ ID No: 328	SEQ ID No: 329
BTF3	141	195889	basic transcription factor 3	SEQ ID No: 330		SEQ ID No: 331
BUB3	142	198903	bub3 budding uninhibited by	SEQ ID No: 332	SEQ ID No: 333	SEQ ID No: 334
			benzimidazoles 3 homolog (yeast)
	143	199837	homo sapiens transcribed sequence with	SEQ ID No: 335
			strong similarity to protein sp: p08865
			(h. sapiens) rsp4_human 40s ribosomal
			protein sa (p40) (34/67 kda laminin
			receptor) (colon carcinoma laminin-
			binding protein) (nem/1chd4)
OAS1	144	200521	2′,5′-oligoadenylate synthetase 1,	SEQ ID No: 336	SEQ ID No: 337	SEQ ID No: 338
			40/46 kda
CD209L	145	200714	cd209 antigen-like	SEQ ID No: 339	SEQ ID No: 340	SEQ ID No: 341
FGB	146	201352	fibrinogen, b beta polypeptide	SEQ ID No: 342		SEQ ID No: 343
MYL1	147	201925	myosin, light polypeptide 1, alkali;	SEQ ID No: 344	SEQ ID No: 345	SEQ ID No: 346
			skeletal, fast
PRPF4B	148	202609	prp4 pre-mrna processing factor 4	SEQ ID No: 347	SEQ ID No: 348	SEQ ID No: 349
			homolog b (yeast)
ARGBP2	149	203264	arg/abl-interacting protein argbp2	SEQ ID No: 350	SEQ ID No: 351	SEQ ID No: 352
RFC4	150	203275	replication factor c (activator 1) 4,	SEQ ID No: 353	SEQ ID No: 354	SEQ ID No: 355
			37 kda
CSF1R	151	204653	colony stimulating factor 1 receptor,	SEQ ID No: 356	SEQ ID No: 357	SEQ ID No: 358
			formerly mcdonough feline sarcoma
			viral (v-fms) oncogene homolog
	152	204740		SEQ ID No: 359
	153	2048801	homo sapiens mrna full length insert	SEQ ID No: 360
			cdna clone euroimage 1630957
TP53	154	205314	tumor protein p53 (li-fraumeni		SEQ ID No: 361	SEQ ID No: 298
			syndrome)
LRP2	155	2055272	low density lipoprotein-related protein 2	SEQ ID No: 362		SEQ ID No: 363
SP110	156	205612	sp110 nuclear body protein	SEQ ID No: 364	SEQ ID No: 365	SEQ ID No: 366
CCNF	157	206323	cyclin f		SEQ ID No: 367	SEQ ID No: 368
CAPN12	158	206522	calpain 12	SEQ ID No: 369	SEQ ID No: 370
GRB14	159	2067776	growth factor receptor-bound protein 14	SEQ ID No: 371		SEQ ID No: 372
DDX24	160	207491	dead (asp-glu-ala-asp) box polypeptide	SEQ ID No: 373	SEQ ID No: 374	SEQ ID No: 375
			24
	161	208357		SEQ ID No: 376	SEQ ID No: 377
HPN	162	208413	hepsin (transmembrane protease, serine	SEQ ID No: 378	SEQ ID No: 379	SEQ ID No: 380
			1)
MGP	163	209710	matrix gla protein	SEQ ID No: 381		SEQ ID No: 382
	164	2106469	similar to riken cdna 4933405110	SEQ ID No: 383
EPB41L4B	165	210698	erythrocyte membrane protein band 4.1	SEQ ID No: 384	SEQ ID No: 385	SEQ ID No: 386
			like 4b
RPS4X	166	211433	ribosomal protein s4, x-linked	SEQ ID No: 387		SEQ ID No: 388
IGF2	167	211445	insulin-like growth factor 2	SEQ ID No: 389		SEQ ID No: 390
			(somatomedin a)
UBA52	168	211920	ubiquitin a-52 residue ribosomal protein	SEQ ID No: 391	SEQ ID No: 392	SEQ ID No: 393
			fusion product 1
AKR1C3	169	211995	aldo-keto reductase family 1, member		SEQ ID No: 394	SEQ ID No: 395
			c3 (3-alpha hydroxysteroid
			dehydrogenase, type ii)
RARB	170	212414	retinoic acid receptor, beta	SEQ ID No: 396	SEQ ID No: 397	SEQ ID No: 398
MGLL	171	21626	monoglyceride lipase	SEQ ID No: 399		SEQ ID No: 400
CRK	172	22295	v-crk sarcoma virus ct10 oncogene		SEQ ID No: 401	SEQ ID No: 402
			homolog (avian)
LAMA3	173	2266576	laminin, alpha 3	SEQ ID No: 403		SEQ ID No: 404
ZDHHC1	174	2272404	zinc finger, dhhc domain containing 1	SEQ ID No: 405		SEQ ID No: 406
BCL2	175	232714	b-cell cll/lymphoma 2	SEQ ID No: 407		SEQ ID No: 408
VPREB3	176	2349125	pre-b lymphocyte gene 3	SEQ ID No: 409		SEQ ID No: 410
PFC	177	235934	properdin p factor, complement	SEQ ID No: 411	SEQ ID No: 412	SEQ ID No: 413
BAK1	178	235938	bcl2-antagonist/killer 1	SEQ ID No: 414	SEQ ID No: 415	SEQ ID No: 416
MGC13071	179	236008	hypothetical protein mgc13071	SEQ ID No: 417	SEQ ID No: 418	SEQ ID No: 419
TP53	180	236338	tumor protein p53 (li-fraumeni	SEQ ID No: 420	SEQ ID No: 421	SEQ ID No: 298
			syndrome)
CAPN2	181	23643	calpain 2, (m/ii) large subunit	SEQ ID No: 422	SEQ ID No: 423	SEQ ID No: 424
ARAF1	182	23692	v-raf murine sarcoma 3611 viral	SEQ ID No: 425	SEQ ID No: 426	SEQ ID No: 427
			oncogene homolog 1
QDPR	183	23776	quinoid dihydropteridine reductase	SEQ ID No: 428	SEQ ID No: 429	SEQ ID No: 430
SLC12A2	184	238612	solute carrier family 12	SEQ ID No: 431	SEQ ID No: 432	SEQ ID No: 433
			(sodium/potassium/chloride
			transporters), member 2
MGC5395	185	238840	hypothetical protein mgc5395	SEQ ID No: 434	SEQ ID No: 435	SEQ ID No: 436
GCSH	186	239937	glycine cleavage system protein h		SEQ ID No: 437	SEQ ID No: 438
			(aminomethyl carrier)
EPHB2	187	24067	ephb2	SEQ ID No: 439		SEQ ID No: 440
	188	240753		SEQ ID No: 441	SEQ ID No: 442
TPP2	189	24085	tripeptidyl peptidase ii	SEQ ID No: 443	SEQ ID No: 444	SEQ ID No: 445
TPP2	190	241151	tripeptidyl peptidase ii	SEQ ID No: 446	SEQ ID No: 447	SEQ ID No: 445
IQGAP1	191	24125	iq motif containing gtpase activating	SEQ ID No: 448	SEQ ID No: 449	SEQ ID No: 450
			protein 1
FGB	192	241788	fibrinogen, b beta polypeptide	SEQ ID No: 451	SEQ ID No: 452	SEQ ID No: 343
FGA	193	244810	fibrinogen, a alpha polypeptide	SEQ ID No: 453		SEQ ID No: 454
CTSS	194	245614	cathepsin s	SEQ ID No: 455	SEQ ID No: 456	SEQ ID No: 457
FAM3A	195	24609	family with sequence similarity 3,	SEQ ID No: 458	SEQ ID No: 459	SEQ ID No: 460
			member a
GSN	196	246170	gelsolin (amyloidosis, finnish type)	SEQ ID No: 461	SEQ ID No: 462	SEQ ID No: 463
IDE	197	246290	insulin-degrading enzyme	SEQ ID No: 464		SEQ ID No: 465
ADH4	198	246860	alcohol dehydrogenase 4 (class ii), pi	SEQ ID No: 466	SEQ ID No: 467	SEQ ID No: 468
			polypeptide
DSC2	199	247055	desmocollin 2	SEQ ID No: 469	SEQ ID No: 470	SEQ ID No: 471
K-ALPHA-1	200	247905	tubulin, alpha, ubiquitous	SEQ ID No: 472		SEQ ID No: 473
ATP6V1H	201	247909	atpase, h+ transporting, lysosomal	SEQ ID No: 474		SEQ ID No: 475
			50/57 kda, v1 subunit h
COX5B	202	248263	cytochrome c oxidase subunit vb	SEQ ID No: 476	SEQ ID No: 477	SEQ ID No: 478
DLK1	203	248701	delta-like 1 homolog (drosophila)	SEQ ID No: 479		SEQ ID No: 480
CNTN1	204	24884	contactin 1	SEQ ID No: 481	SEQ ID No: 482	SEQ ID No: 483
CDC42	205	251772	cell division cycle 42 (gtp binding	SEQ ID No: 484		SEQ ID No: 485
			protein, 25 kda)
SCO1	206	25222	sco cytochrome oxidase deficient	SEQ ID No: 486		SEQ ID No: 487
			homolog 1 (yeast)
LOC51058	207	25285	hypothetical protein loc51058	SEQ ID No: 488		SEQ ID No: 489
RALB	208	25392	v-ral simian leukemia viral oncogene	SEQ ID No: 490	SEQ ID No: 491	SEQ ID No: 492
			homolog b (ras related; gtp binding
			protein)
RPL3	209	254505	ribosomal protein 13	SEQ ID No: 493		SEQ ID No: 494
SLPI	210	255348	secretory leukocyte protease inhibitor	SEQ ID No: 495		SEQ ID No: 496
			(antileukoproteinase)
HIPK3	211	256846	homeodomain interacting protein kinase 3	SEQ ID No: 497	SEQ ID No: 498	SEQ ID No: 499
NIT1	212	257170	nitrilase 1	SEQ ID No: 500	SEQ ID No: 501	SEQ ID No: 502
RPL39	213	257284	ribosomal protein 139	SEQ ID No: 503		SEQ ID No: 504
UCHL3	214	257445	ubiquitin carboxyl-terminal esterase 13	SEQ ID No: 505	SEQ ID No: 506	SEQ ID No: 507
			(ubiquitin thiolesterase)
MAD	215	257519	max dimerization protein 1	SEQ ID No: 508		SEQ ID No: 509
DUSP1	216	257708	dual specificity phosphatase 1	SEQ ID No: 510		SEQ ID No: 511
COX7B	217	258313	cytochrome c oxidase subunit viib	SEQ ID No: 512		SEQ ID No: 513
KRT6B	218	25831	keratin 6b	SEQ ID No: 514	SEQ ID No: 515	SEQ ID No: 516
CYP19A1	219	258870	cytochrome p450, family 19, subfamily	SEQ ID No: 517	SEQ ID No: 518	SEQ ID No: 519
			a, polypeptide 1
HPSE	220	260138	heparanase	SEQ ID No: 520	SEQ ID No: 521	SEQ ID No: 522
CTCF	221	26029	ccctc-binding factor (zinc finger	SEQ ID No: 523	SEQ ID No: 524	SEQ ID No: 525
			protein)
HMGA2	222	261204	high mobility group at-hook 2	SEQ ID No: 526		SEQ ID No: 527
CTSB	223	261517	cathepsin b	SEQ ID No: 528		SEQ ID No: 529
GK	224	262425	glycerol kinase		SEQ ID No: 530	SEQ ID No: 531
IL6ST	225	263262	interleukin 6 signal transducer (gp 130,	SEQ ID No: 532		SEQ ID No: 533
			oncostatin m receptor)
C5ORF5	226	264183	chromosome 5 open reading frame 5	SEQ ID No: 534	SEQ ID No: 535	SEQ ID No: 536
LOC57209	227	264186	kruppel-type zinc finger protein	SEQ ID No: 537	SEQ ID No: 538
CRYAB	228	264331	crystallin, alpha b	SEQ ID No: 539	SEQ ID No: 540	SEQ ID No: 541
MGC9850	229	26584	hypothetical protein mgc9850	SEQ ID No: 542		SEQ ID No: 543
CCT4	230	26710	chaperonin containing tcpl, subunit 4	SEQ ID No: 544	SEQ ID No: 545	SEQ ID No: 546
			(delta)
LIAS	231	267123	lipoic acid synthetase	SEQ ID No: 547	SEQ ID No: 548	SEQ ID No: 549
HMGB2	232	267145	high-mobility group box 2	SEQ ID No: 550	SEQ ID No: 551	SEQ ID No: 552
MAGEH1	233	267657	apr-1 protein	SEQ ID No: 553	SEQ ID No: 554	SEQ ID No: 555
MADH1	234	268150	mad, mothers against decapentaplegic	SEQ ID No: 556	SEQ ID No: 557	SEQ ID No: 558
			homolog 1 (drosophila)
ACADVL	235	269388	acyl-coenzyme a dehydrogenase, very	SEQ ID No: 559		SEQ ID No: 560
			long chain
RENT1	236	26945	regulator of nonsense transcripts 1	SEQ ID No: 561	SEQ ID No: 562	SEQ ID No: 563
PWP1	237	26964	nuclear phosphoprotein similar to	SEQ ID No: 564	SEQ ID No: 565	SEQ ID No: 566
			s. cerevisiae pwp1
PTD004	238	270794	hypothetical protein ptd004	SEQ ID No: 567	SEQ ID No: 568	SEQ ID No: 569
	239	27100		SEQ ID No: 570	SEQ ID No: 571
ASNS	240	27208	asparagine synthetase	SEQ ID No: 572	SEQ ID No: 573	SEQ ID No: 574
NRAS	241	272189	neuroblastoma ras viral (v-ras)	SEQ ID No: 575	SEQ ID No: 576	SEQ ID No: 577
			oncogene homolog
MORF4L1	242	27237	mortality factor 4 like 1	SEQ ID No: 578		SEQ ID No: 579
CCT4	243	272502	chaperonin containing tcp1, subunit 4	SEQ ID No: 580		SEQ ID No: 546
			(delta)
WBSCR22	244	27326	williams beuren syndrome chromosome	SEQ ID No: 581	SEQ ID No: 582	SEQ ID No: 583
			region 22
GNS	245	274315	glucosamine (n-acetyl)-6-sulfatase	SEQ ID No: 584	SEQ ID No: 585	SEQ ID No: 586
			(sanfilippo disease iiid)
SLC17A7	246	27506	solute carrier family 17 (sodium-	SEQ ID No: 587		SEQ ID No: 588
			dependent inorganic phosphate
			cotransporter), member 7
ARHT2	247	27599	ras homolog gene family, member t2	SEQ ID No: 589	SEQ ID No: 590	SEQ ID No: 591
TP53BP2	248	277339	tumor protein p53 binding protein, 2	SEQ ID No: 592	SEQ ID No: 593	SEQ ID No: 594
CCBL1	249	277740	cysteine conjugate-beta lyase;	SEQ ID No: 595	SEQ ID No: 596	SEQ ID No: 597
			cytoplasmic (glutamine transaminase k,
			kyneurenine aminotransferase)
ID4	250	2783684	inhibitor of dna binding 4, dominant	SEQ ID No: 598	SEQ ID No: 599	SEQ ID No: 600
			negative helix-loop-helix protein
TUBE1	251	279460	tubulin, epsilon 1	SEQ ID No: 601	SEQ ID No: 602	SEQ ID No: 603
MPDZ	252	28019	multiple pdz domain protein	SEQ ID No: 604	SEQ ID No: 605	SEQ ID No: 606
CACNA1I	253	283375	calcium channel, voltage-dependent,	SEQ ID No: 607	SEQ ID No: 608	SEQ ID No: 609
			alpha 1i subunit
GFER	254	283601	growth factor, augmenter of liver	SEQ ID No: 610	SEQ ID No: 611	SEQ ID No: 612
			regeneration (erv1 homolog, s. cerevisiae
SNRPB2	255	284256	small nuclear ribonucleoprotein	SEQ ID No: 613		SEQ ID No: 614
			polypeptide b″
CHI3L2	256	284640	chitinase 3-like 2	SEQ ID No: 615		SEQ ID No: 616
ABCA8	257	284828	atp-binding cassette, sub-family a	SEQ ID No: 617		SEQ ID No: 618
			(abc1), member 8
BTBD1	258	28577	btb (poz) domain containing 1	SEQ ID No: 619	SEQ ID No: 620	SEQ ID No: 621
MMP13	259	285780	matrix metalloproteinase 13	SEQ ID No: 622		SEQ ID No: 623
			(collagenase 3)
GART	260	28596	phosphoribosylglycinamide	SEQ ID No: 624	SEQ ID No: 625	SEQ ID No: 626
			formyltransferase,
			phosphoribosylglycinamide synthetase,
			phosphoribosylaminoimidazole
			synthetase
CUL2	261	286287	cullin 2	SEQ ID No: 627		SEQ ID No: 628
GRM3	262	287843	glutamate receptor, metabotropic 3	SEQ ID No: 629		SEQ ID No: 630
CA7	263	288874	carbonic anhydrase vii	SEQ ID No: 631	SEQ ID No: 632	SEQ ID No: 633
PNMT	264	289857	phenylethanolamine n-	SEQ ID No: 634		SEQ ID No: 635
			methyltransferase
SILV	265	291448	silver homolog (mouse)	SEQ ID No: 636	SEQ ID No: 637	SEQ ID No: 638
ANK1	266	292321	ankyrin 1, erythrocytic	SEQ ID No: 639	SEQ ID No: 640	SEQ ID No: 641
XRCC1	267	29451	x-ray repair complementing defective	SEQ ID No: 642	SEQ ID No: 643	SEQ ID No: 644
			repair in chinese hamster cells 1
CSE1L	268	29933	cse1 chromosome segregation 1-like	SEQ ID No: 645	SEQ ID No: 646	SEQ ID No: 647
			(yeast)
DXS1283E	269	300163	gs2 gene	SEQ ID No: 648	SEQ ID No: 649
TAF10	270	30066	taf10 rna polymerase ii, tata box	SEQ ID No: 650		SEQ ID No: 651
			binding protein (tbp)-associated factor,
			30 kda
CKMT2	271	301119	creatine kinase, mitochondrial 2	SEQ ID No: 652	SEQ ID No: 653	SEQ ID No: 654
			(sarcomeric)
TNNC1	272	301128	troponin c, slow	SEQ ID No: 655		SEQ ID No: 656
DKFZP434J0617	273	301258	hypothetical protein dkfzp434j0617	SEQ ID No: 657
	274	302310	homo sapiens cdna flj36340 fis, clone	SEQ ID No: 658	SEQ ID No: 659
			thymu2006468.
GUK1	275	302453	guanylate kinase 1		SEQ ID No: 660	SEQ ID No: 661
HSPA9B	276	305045	heat shock 70 kda protein 9b (mortalin-	SEQ ID No: 662	SEQ ID No: 663	SEQ ID No: 664
			2)
NDUFA6	277	306510	nadh dehydrogenase (ubiquinone) 1	SEQ ID No: 665	SEQ ID No: 666	SEQ ID No: 667
			alpha subcomplex, 6, 14 kda
IFNGR2	278	306555	interferon gamma receptor 2 (interferon	SEQ ID No: 668	SEQ ID No: 669	SEQ ID No: 670
			gamma transducer 1)
HRIHFB2206	279	306697	hrihfb2206 protein	SEQ ID No: 671	SEQ ID No: 672
GCAT	280	307094	glycine c-acetyltransferase (2-amino-3-	SEQ ID No: 673	SEQ ID No: 674	SEQ ID No: 675
			ketobutyrate coenzyme a ligase)
CD9	281	307352	cd9 antigen (p24)	SEQ ID No: 676	SEQ ID No: 677	SEQ ID No: 678
ESD	282	310057	esterase d/formylglutathione hydrolase	SEQ ID No: 679	SEQ ID No: 680
ZNF183	283	310088	zinc finger protein 183 (ring finger,	SEQ ID No: 681	SEQ ID No: 682	SEQ ID No: 683
			c3hc4 type)
HSPA8	284	31027	heat shock 70 kda protein 8	SEQ ID No: 684	SEQ ID No: 685	SEQ ID No: 686
RPL35	285	310774	ribosomal protein 135	SEQ ID No: 687	SEQ ID No: 688	SEQ ID No: 689
NUDT5	286	310860	nudix (nucleoside diphosphate linked	SEQ ID No: 690	SEQ ID No: 691	SEQ ID No: 692
			moiety x)-type motif 5
PFDN4	287	320143	prefoldin 4	SEQ ID No: 693	SEQ ID No: 694	SEQ ID No: 695
RPL37	288	320151	ribosomal protein 137	SEQ ID No: 696	SEQ ID No: 697	SEQ ID No: 698
SPR	289	320457	sepiapterin reductase (7,8-	SEQ ID No: 699	SEQ ID No: 700	SEQ ID No: 701
			dihydrobiopterin:nadp +
			oxidoreductase)
LOC56267	290	320775	hypothetical protein 669	SEQ ID No: 702	SEQ ID No: 703	SEQ ID No: 704
RPL31	291	321259	ribosomal protein 131	SEQ ID No: 705	SEQ ID No: 706	SEQ ID No: 707
SRP72	292	321510	signal recognition particle 72 kda	SEQ ID No: 708	SEQ ID No: 709	SEQ ID No: 710
RPS6	293	321733	ribosomal protein s6	SEQ ID No: 711	SEQ ID No: 712	SEQ ID No: 713
PHKG1	294	321783	phosphorylase kinase, gamma 1	SEQ ID No: 714	SEQ ID No: 715	SEQ ID No: 716
			(muscle)
TACSTD1	295	321907	tumor-associated calcium signal	SEQ ID No: 717	SEQ ID No: 718	SEQ ID No: 719
			transducer 1
RPS27L	296	321973	ribosomal protein s27-like	SEQ ID No: 720	SEQ ID No: 721	SEQ ID No: 722
	297	321981	loc151103	SEQ ID No: 723	SEQ ID No: 724
CHGA	298	322452	chromogranin a (parathyroid secretory	SEQ ID No: 725	SEQ ID No: 726	SEQ ID No: 727
			protein 1)
SNRPC	299	322471	small nuclear ribonucleoprotein	SEQ ID No: 728	SEQ ID No: 729	SEQ ID No: 730
			polypeptide c
AIP	300	322495	aryl hydrocarbon receptor interacting	SEQ ID No: 731	SEQ ID No: 732	SEQ ID No: 733
			protein
IRF1	301	323001	interferon regulatory factor 1	SEQ ID No: 734	SEQ ID No: 735	SEQ ID No: 736
COX7A2	302	323650	cytochrome c oxidase subunit viia	SEQ ID No: 737	SEQ ID No: 738	SEQ ID No: 739
			polypeptide 2 (liver)
LOC51255	303	323681	hypothetical protein loc51255	SEQ ID No: 740	SEQ ID No: 741	SEQ ID No: 742
COPZ2	304	323753	coatomer protein complex, subunit zeta 2	SEQ ID No: 743	SEQ ID No: 744	SEQ ID No: 745
CKAP1	305	323766	cytoskeleton-associated protein 1	SEQ ID No: 746		SEQ ID No: 747
RPS3A	306	323863	ribosomal protein s3a	SEQ ID No: 748	SEQ ID No: 749	SEQ ID No: 750
SOX9	307	323948	sry (sex determining region y)-box 9	SEQ ID No: 751		SEQ ID No: 752
			(campomelic dysplasia, autosomal sex-
			reversal)
DSCR1	308	324006	down syndrome critical region gene 1	SEQ ID No: 753	SEQ ID No: 754	SEQ ID No: 755
KRAS2	309	324257	v-ki-ras2 kirsten rat sarcoma 2 viral	SEQ ID No: 756	SEQ ID No: 757	SEQ ID No: 758
			oncogene homolog
CTBS	310	324369	chitobiase, di-n-acetyl-	SEQ ID No: 759		SEQ ID No: 760
PPP1R15A	311	324684	protein phosphatase 1, regulatory	SEQ ID No: 761	SEQ ID No: 762	SEQ ID No: 763
			(inhibitor) subunit 15a
RPS15A	312	324757	ribosomal protein s15a	SEQ ID No: 764	SEQ ID No: 765	SEQ ID No: 311
SAT	313	324930	spermidine/spermine n1-	SEQ ID No: 766	SEQ ID No: 767	SEQ ID No: 768
			acetyltransferase
GRSF1	314	325058	g-rich rna sequence binding factor 1	SEQ ID No: 769	SEQ ID No: 770	SEQ ID No: 771
PSG5	315	325641	pregnancy specific beta-1-glycoprotein 5	SEQ ID No: 772	SEQ ID No: 773	SEQ ID No: 774
STMN4	316	32698	stathmin-like 4	SEQ ID No: 775	SEQ ID No: 776	SEQ ID No: 777
CDH15	317	327684	cadherin 15, m-cadherin (myotubule)	SEQ ID No: 778	SEQ ID No: 779	SEQ ID No: 780
NDUFA4	318	327740	nadh dehydrogenase (ubiquinone) 1	SEQ ID No: 781	SEQ ID No: 782	SEQ ID No: 320
			alpha subcomplex, 4, 9 kda
RAN	319	328245	ran, member ras oncogene family	SEQ ID No: 783	SEQ ID No: 784	SEQ ID No: 785
PNLIPRP1	320	328591	pancreatic lipase-related protein 1	SEQ ID No: 786	SEQ ID No: 787	SEQ ID No: 788
CAP2	321	33005	cap, adenylate cyclase-associated	SEQ ID No: 789	SEQ ID No: 790	SEQ ID No: 791
			protein, 2 (yeast)
NDFIP2	322	33722	nedd4 family interacting protein 2		SEQ ID No: 792
ATP5C1	323	33794	atp synthase, h+ transporting,	SEQ ID No: 793	SEQ ID No: 794	SEQ ID No: 109
			mitochondrial f1 complex, gamma
			polypeptide 1
ATP7A	324	340995	atpase, cu++ transporting, alpha	SEQ ID No: 795	SEQ ID No: 796	SEQ ID No: 797
			polypeptide (menkes syndrome)
ATP6V0B	325	341121	atpase, h+ transporting, lysosomal	SEQ ID No: 798	SEQ ID No: 799	SEQ ID No: 800
			21 kda, v0 subunit c″
DAD1	326	341699	defender against cell death 1	SEQ ID No: 801	SEQ ID No: 802	SEQ ID No: 803
	327	341834	loc349507	SEQ ID No: 804	SEQ ID No: 805
	328	341984		SEQ ID No: 806	SEQ ID No: 807
CXORF6	329	342054	chromosome x open reading frame 6	SEQ ID No: 808	SEQ ID No: 809	SEQ ID No: 810
B2M	330	342416	beta-2-microglobulin	SEQ ID No: 811	SEQ ID No: 812	SEQ ID No: 813
CLIC5	331	34260	chloride intracellular channel 5	SEQ ID No: 814	SEQ ID No: 815	SEQ ID No: 816
NDN	332	343578	necdin homolog (mouse)	SEQ ID No: 817	SEQ ID No: 818	SEQ ID No: 819
OSBPL1A	333	344037	oxysterol binding protein-like 1a	SEQ ID No: 820	SEQ ID No: 821	SEQ ID No: 822
COL6A1	334	344326	collagen, type vi, alpha 1	SEQ ID No: 823	SEQ ID No: 824	SEQ ID No: 825
MRPS23	335	344792	mitochondrial ribosomal protein s23	SEQ ID No: 826	SEQ ID No: 827	SEQ ID No: 828
PIK3CA	336	345430	phosphoinositide-3-kinase, catalytic,	SEQ ID No: 829	SEQ ID No: 830	SEQ ID No: 831
			alpha polypeptide
C6ORF9	337	345437	chromosome 6 open reading frame 9	SEQ ID No: 832	SEQ ID No: 833	SEQ ID No: 834
FLJ20813	338	345648	hypothetical protein flj20813	SEQ ID No: 835	SEQ ID No: 836	SEQ ID No: 837
RPS21	339	345676	ribosomal protein s21	SEQ ID No: 838	SEQ ID No: 839	SEQ ID No: 840
	340	345694		SEQ ID No: 841	SEQ ID No: 842
CA3	341	345706	carbonic anhydrase iii, muscle specific	SEQ ID No: 843	SEQ ID No: 844	SEQ ID No: 845
P4HA1	342	346016	procollagen-proline, 2-oxoglutarate 4-	SEQ ID No: 846	SEQ ID No: 847	SEQ ID No: 848
			dioxygenase (proline 4-hydroxylase),
			alpha polypeptide i
COL6A2	343	346269	collagen, type vi, alpha 2	SEQ ID No: 849	SEQ ID No: 850	SEQ ID No: 851
SFN	344	346610	Stratifin	SEQ ID No: 852	SEQ ID No: 853	SEQ ID No: 854
TCEB1	345	347373	transcription elongation factor b (siii),	SEQ ID No: 855	SEQ ID No: 856	SEQ ID No: 857
			polypeptide 1 (15 kda, elongin c)
RELN	346	34888	Reelin	SEQ ID No: 858	SEQ ID No: 859	SEQ ID No: 860
SKP1A	347	34917	s-phase kinase-associated protein 1a	SEQ ID No: 861	SEQ ID No: 862	SEQ ID No: 863
			(p19a)
AQP1	348	35072	aquaporin 1 (channel-forming integral	SEQ ID No: 864	SEQ ID No: 865	SEQ ID No: 866
			protein, 28 kda)
IRF2	349	35262	interferon regulatory factor 2	SEQ ID No: 867	SEQ ID No: 868	SEQ ID No: 869
NGB	350	35483	Neuroglobin	SEQ ID No: 870	SEQ ID No: 871	SEQ ID No: 872
TM4SF5	351	356783	transmembrane 4 superfamily member 5	SEQ ID No: 873	SEQ ID No: 874	SEQ ID No: 875
TGFB3	352	356980	transforming growth factor, beta 3	SEQ ID No: 876	SEQ ID No: 877	SEQ ID No: 878
RPA3	353	357239	replication protein a3, 14 kda	SEQ ID No: 879	SEQ ID No: 880	SEQ ID No: 881
SEMA3C	354	357820	sema domain, immunoglobulin domain	SEQ ID No: 882	SEQ ID No: 883	SEQ ID No: 884
			(ig), short basic domain, secreted,
			(semaphorin) 3c
CNOT2	355	357893	ccr4-not transcription complex, subunit 2	SEQ ID No: 885		SEQ ID No: 886
CDW52	356	358041	cdw52 antigen (campath-1 antigen)	SEQ ID No: 887	SEQ ID No: 888	SEQ ID No: 889
SOX9	357	358117	sry (sex determining region y)-box 9	SEQ ID No: 890	SEQ ID No: 891	SEQ ID No: 752
			(campomelic dysplasia, autosomal sex-
			reversal)
HSU79266	358	358162	protein predicted by clone 23627	SEQ ID No: 892	SEQ ID No: 893	SEQ ID No: 894
PFDN2	359	358267	prefoldin 2	SEQ ID No: 895	SEQ ID No: 896	SEQ ID No: 897
TPM1	360	358683	tropomyosin 1 (alpha)	SEQ ID No: 898	SEQ ID No: 899	SEQ ID No: 900
FLJ21272	361	358943	hypothetical protein flj21272	SEQ ID No: 901	SEQ ID No: 902	SEQ ID No: 903
PSMC2	362	358993	proteasome (prosome, macropain) 26s	SEQ ID No: 904		SEQ ID No: 905
			subunit, atpase, 2
CKS2	363	359119	cdc28 protein kinase regulatory subunit 2	SEQ ID No: 906		SEQ ID No: 907
NDUFA9	364	359147	nadh dehydrogenase (ubiquinone) 1	SEQ ID No: 908		SEQ ID No: 909
			alpha subcomplex, 9, 39 kda
H11	365	359191	protein kinase h11	SEQ ID No: 910		SEQ ID No: 911
CA4	366	359250	carbonic anhydrase iv	SEQ ID No: 912	SEQ ID No: 913	SEQ ID No: 914
PRSS3	367	359254	protease, serine, 3 (mesotrypsin)	SEQ ID No: 915	SEQ ID No: 916	SEQ ID No: 917
	368	360588	homo sapiens transcribed sequence with	SEQ ID No: 918
			moderate similarity to protein
			ref: np_036199.1 (h. sapiens) aldo-keto
			reductase family 7, member a3
			(aflatoxin aldehyde reductase) [homo
			sapiens]
HIG1	369	361108	likely ortholog of mouse hypoxia	SEQ ID No: 919	SEQ ID No: 920	SEQ ID No: 921
			induced gene 1
	370	363273		SEQ ID No: 922	SEQ ID No: 923
ADD1	371	363991	adducin 1 (alpha)	SEQ ID No: 924	SEQ ID No: 925	SEQ ID No: 68
LAMB1	372	364012	laminin, beta 1	SEQ ID No: 926	SEQ ID No: 927	SEQ ID No: 928
CD5	373	364687	cd5 antigen (p56-62)	SEQ ID No: 929	SEQ ID No: 930	SEQ ID No: 931
UQCR	374	36607	ubiquinol-cytochrome c reductase	SEQ ID No: 932	SEQ ID No: 933	SEQ ID No: 934
			(6.4 kd) subunit
RAP2A	375	36684	rap2a, member of ras oncogene family	SEQ ID No: 935	SEQ ID No: 936	SEQ ID No: 937
RGS6	376	36710	regulator of g-protein signalling 6	SEQ ID No: 938	SEQ ID No: 939	SEQ ID No: 940
IL1RN	377	36844	interleukin 1 receptor antagonist	SEQ ID No: 941	SEQ ID No: 942	SEQ ID No: 943
LRP1	378	37345	low density lipoprotein-related protein	SEQ ID No: 944	SEQ ID No: 945	SEQ ID No: 946
			1 (alpha-2-macroglobulin receptor)
DJ1042K10.2	379	37496	hypothetical protein dj1042k10.2	SEQ ID No: 947	SEQ ID No: 948	SEQ ID No: 949
PTPRN2	380	37506	protein tyrosine phosphatase, receptor	SEQ ID No: 950	SEQ ID No: 951	SEQ ID No: 952
			type, n polypeptide 2
CCNB2	381	375781	cyclin b2	SEQ ID No: 953	SEQ ID No: 954	SEQ ID No: 955
TCTEL1	382	376284	t-complex-associated-testis-expressed	SEQ ID No: 956	SEQ ID No: 957	SEQ ID No: 958
			1-like 1
TUBB	383	37630	tubulin, beta polypeptide	SEQ ID No: 959		SEQ ID No: 960
RHEB	384	376473	ras homolog enriched in brain	SEQ ID No: 961	SEQ ID No: 962	SEQ ID No: 963
VCP	385	376547	valosin-containing protein	SEQ ID No: 964		SEQ ID No: 965
IL2RB	386	376696	interleukin 2 receptor, beta	SEQ ID No: 966	SEQ ID No: 967	SEQ ID No: 152
TAZ	387	376755	transcriptional co-activator with pdz-	SEQ ID No: 968	SEQ ID No: 969	SEQ ID No: 970
			binding motif (taz)
HSPC150	388	376769	hspc150 protein similar to ubiquitin-	SEQ ID No: 971	SEQ ID No: 972	SEQ ID No: 973
			conjugating enzyme
PLCD4	389	376802	phospholipase c, delta 4	SEQ ID No: 974	SEQ ID No: 975	SEQ ID No: 976
NR2F6	390	377020	nuclear receptor subfamily 2, group f,		SEQ ID No: 977	SEQ ID No: 978
			member 6
MTPN	391	377545	Myotrophin	SEQ ID No: 979		SEQ ID No: 980
SLPI	392	378813	secretory leukocyte protease inhibitor	SEQ ID No: 981		SEQ ID No: 496
			(antileukoproteinase)
KPNA1	393	38056	karyopherin alpha 1 (importin alpha 5)	SEQ ID No: 982	SEQ ID No: 983	SEQ ID No: 984
LAMR1	394	383433	laminin receptor 1 (ribosomal protein	SEQ ID No: 985	SEQ ID No: 986	SEQ ID No: 987
			sa, 67 kda)
SST	395	39593	Somatostatin	SEQ ID No: 988		SEQ ID No: 989
ABCA5	396	39821	atp-binding cassette, sub-family a	SEQ ID No: 990	SEQ ID No: 991	SEQ ID No: 992
			(abc1), member 5
NME1	397	39961	non-metastatic cells 1, protein (nm23a)	SEQ ID No: 993	SEQ ID No: 994	SEQ ID No: 288
			expressed in
ADAM23	398	39972	a disintegrin and metalloproteinase	SEQ ID No: 995	SEQ ID No: 996	SEQ ID No: 997
			domain 23
CYCS	399	40017	cytochrome c, somatic	SEQ ID No: 998	SEQ ID No: 999	SEQ ID No: 1000
GCNIL1	400	40567	gcn1 general control of amino-acid	SEQ ID No: 1001	SEQ ID No: 1002
			synthesis 1-like 1 (yeast)
RBBP1	401	40721	retinoblastoma binding protein 1	SEQ ID No: 1003	SEQ ID No: 1004	SEQ ID No: 1005
CNN3	402	41099	calponin 3, acidic	SEQ ID No: 1006	SEQ ID No: 1007	SEQ ID No: 1008
RPL24	403	41411	ribosomal protein 124	SEQ ID No: 1009	SEQ ID No: 1010	SEQ ID No: 1011
SAT	404	41452	spermidine/spermine n1-	SEQ ID No: 1012	SEQ ID No: 1013	SEQ ID No: 768
			acetyltransferase
SNRPE	405	415389	small nuclear ribonucleoprotein	SEQ ID No: 1014	SEQ ID No: 1015	SEQ ID No: 1016
			polypeptide e
ARG1	406	416060	arginase, liver	SEQ ID No: 1017	SEQ ID No: 1018	SEQ ID No: 1019
IL13RA2	407	41648	interleukin 13 receptor, alpha 2	SEQ ID No: 1020	SEQ ID No: 1021	SEQ ID No: 1022
TXN	408	416946	Thioredoxin	SEQ ID No: 1023	SEQ ID No: 1024	SEQ ID No: 1025
TFR2	409	417861	transferrin receptor 2	SEQ ID No: 1026	SEQ ID No: 1027	SEQ ID No: 1028
NUTF2	410	41857	nuclear transport factor 2	SEQ ID No: 1029		SEQ ID No: 1030
P2RX4	411	42118	purinergic receptor p2x, ligand-gated	SEQ ID No: 1031	SEQ ID No: 1032	SEQ ID No: 1033
			ion channel, 4
SYK	412	42214	spleen tyrosine kinase	SEQ ID No: 1034	SEQ ID No: 1035	SEQ ID No: 1036
GPC6	413	427858	glypican 6	SEQ ID No: 1037	SEQ ID No: 1038	SEQ ID No: 1039
CD1C	414	428103	cd1c antigen, c polypeptide	SEQ ID No: 1040	SEQ ID No: 1041	SEQ ID No: 1042
CYCS	415	429544	cytochrome c, somatic	SEQ ID No: 1043	SEQ ID No: 1044	SEQ ID No: 1000
TNFRSF7	416	430090	tumor necrosis factor receptor	SEQ ID No: 1045	SEQ ID No: 1046	SEQ ID No: 1047
			superfamily, member 7
	417	43207	homo sapiens transcribed sequence with	SEQ ID No: 1048	SEQ ID No: 1049
			strong similarity to protein sp: o00451
			(h. sapiens) nrtr_human neurturin
			receptor alpha precursor (ntnr-alpha)
			(nrtnr-alpha) (tgf-beta related
			neurotrophic factor receptor 2) (gdnf
			receptor beta) (gdnfr-beta) (ret ligand 2)
			(gfr-alpha 2)
GALNACT-2	418	43276	chondroitin sulfate galnact-2	SEQ ID No: 1050		SEQ ID No: 1051
F5	419	433155	coagulation factor v (proaccelerin,	SEQ ID No: 1052		SEQ ID No: 1053
			labile factor)
	420	43338	homo sapiens transcribed sequence with	SEQ ID No: 1054
			moderate similarity to protein
			ref: np_004491.1 (h. sapiens)
			heterogeneous nuclear
			ribonucleoprotein c, isoform b; nuclear
			ribonucleoprotein particle c1 protein;
			nuclear ribonucleoprotein particle c2
			protein [homo sapiens]
RPL15	421	43442	ribosomal protein 115	SEQ ID No: 1055		SEQ ID No: 1056
RPS28	422	43493	ribosomal protein s28	SEQ ID No: 1057	SEQ ID No: 1058	SEQ ID No: 1059
LDHA	423	43550	lactate dehydrogenase a	SEQ ID No: 1060		SEQ ID No: 1061
RAN	424	43638	ran, member ras oncogene family	SEQ ID No: 1062	SEQ ID No: 1063	SEQ ID No: 785
PPP2CA	425	43760	protein phosphatase 2 (formerly 2a),	SEQ ID No: 1064	SEQ ID No: 1065	SEQ ID No: 1066
			catalytic subunit, alpha isoform
CSNK2A1	426	43941	casein kinase 2, alpha 1 polypeptide	SEQ ID No: 1067	SEQ ID No: 1068	SEQ ID No: 1069
CCT3	427	44152	chaperonin containing tcp1, subunit 3	SEQ ID No: 1070	SEQ ID No: 1071	SEQ ID No: 1072
			(gamma)
LOC115286	428	45021	hypothetical protein loc115286	SEQ ID No: 1073	SEQ ID No: 1074	SEQ ID No: 1075
SNCA	429	45086	synuclein, alpha (non a4 component of	SEQ ID No: 1076	SEQ ID No: 1077	SEQ ID No: 1078
			amyloid precursor)
MORF4L2	430	45706	mortality factor 4 like 2	SEQ ID No: 1079		SEQ ID No: 1080
YWHAB	431	45831	tyrosine 3-monooxygenase/tryptophan	SEQ ID No: 1081	SEQ ID No: 1082	SEQ ID No: 1083
			5-monooxygenase activation protein,
			beta polypeptide
PCSK7	432	45900	proprotein convertase subtilisin/kexin	SEQ ID No: 1084		SEQ ID No: 1085
			type 7
COX7A2L	433	46147	cytochrome c oxidase subunit viia	SEQ ID No: 1086	SEQ ID No: 1087	SEQ ID No: 117
			polypeptide 2 like
DTNA	434	46518	dystrobrevin, alpha	SEQ ID No: 1088	SEQ ID No: 1089	SEQ ID No: 1090
PPP1R7	435	46888	protein phosphatase 1, regulatory	SEQ ID No: 1091	SEQ ID No: 1092	SEQ ID No: 1093
			subunit 7
KCNMB1	436	470122	potassium large conductance calcium-	SEQ ID No: 1094	SEQ ID No: 1095	SEQ ID No: 1096
			activated channel, subfamily m, beta
			member 1
MTCP1	437	470175	mature t-cell proliferation 1	SEQ ID No: 1097	SEQ ID No: 1098	SEQ ID No: 1099
CNTNAP1	438	470279	contactin associated protein 1	SEQ ID No: 1100		SEQ ID No: 1101
LOC90139	439	470819	tetraspanin similiar to uroplakin 1	SEQ ID No: 1102		SEQ ID No: 1103
MRE11A	440	471256	mre11 meiotic recombination 11	SEQ ID No: 1104	SEQ ID No: 1105	SEQ ID No: 1106
			homolog a (s. cerevisiae)
ICAM2	441	471918	intercellular adhesion molecule 2	SEQ ID No: 1107		SEQ ID No: 1108
BZRP	442	472021	benzodiazapine receptor (peripheral)	SEQ ID No: 1109	SEQ ID No: 1110	SEQ ID No: 1111
	443	47986			SEQ ID No: 1112
ITGB3	444	484874	integrin, beta 3 (platelet glycoprotein	SEQ ID No: 1113		SEQ ID No: 1114
			iiia, antigen cd61)
	445	485742	similar to hypothetical protein	SEQ ID No: 1115	SEQ ID No: 1116
			bc015353
CABC1	446	486151	chaperone, abc1 activity of bc1	SEQ ID No: 1117	SEQ ID No: 1118	SEQ ID No: 1119
			complex like (s. pombe)
RY1	447	486400	putative nucleic acid binding protein ry-1	SEQ ID No: 1120	SEQ ID No: 1121	SEQ ID No: 1122
CDH13	448	486510	cadherin 13, h-cadherin (heart)	SEQ ID No: 1123	SEQ ID No: 1124	SEQ ID No: 1125
SRP19	449	486702	signal recognition particle 19 kda	SEQ ID No: 1126	SEQ ID No: 1127	SEQ ID No: 1128
MIF	450	488144	macrophage migration inhibitory factor		SEQ ID No: 1129	SEQ ID No: 1130
			(glycosylation-inhibiting factor)
LTBP1	451	488316	latent transforming growth factor beta	SEQ ID No: 1131	SEQ ID No: 1132	SEQ ID No: 1133
			binding protein 1
ZNF354A	452	488412	zinc finger protein 354a	SEQ ID No: 1134	SEQ ID No: 1135	SEQ ID No: 1136
TLE2	453	488430	transducin-like enhancer of split 2	SEQ ID No: 1137	SEQ ID No: 1138	SEQ ID No: 1139
			(e(sp1) homolog, drosophila)
MYH11	454	488526	myosin, heavy polypeptide 11, smooth	SEQ ID No: 1140	SEQ ID No: 1141	SEQ ID No: 1142
			muscle
PIP5K1A	455	488875	phosphatidylinositol-4-phosphate 5-	SEQ ID No: 1143	SEQ ID No: 1144	SEQ ID No: 1145
			kinase, type i, alpha
MFAP3	456	488913	microfibrillar-associated protein 3	SEQ ID No: 1146	SEQ ID No: 1147	SEQ ID No: 1148
GTF2H4	457	489497	general transcription factor iih,	SEQ ID No: 1149	SEQ ID No: 1150	SEQ ID No: 1151
			polypeptide 4, 52 kda
LRPPRC	458	489772	leucine-rich ppr-motif containing	SEQ ID No: 1152	SEQ ID No: 1153	SEQ ID No: 1154
KIAA0232	459	489950	kiaa0232 gene product	SEQ ID No: 1155	SEQ ID No: 1156
GTF2F1	460	489961	general transcription factor iif,	SEQ ID No: 1157	SEQ ID No: 1158	SEQ ID No: 1159
			polypeptide 1, 74 kda
PSMD3	461	490174	proteasome (prosome, macropain) 26s	SEQ ID No: 1160	SEQ ID No: 1161	SEQ ID No: 1162
			subunit, non-atpase, 3
DF	462	491284	d component of complement (adipsin)	SEQ ID No: 1163		SEQ ID No: 1164
PRNP	463	49691	prion protein (p27-30) (creutzfeld-jakob	SEQ ID No: 1165	SEQ ID No: 1166	SEQ ID No: 1167
			disease, gerstmann-strausler-scheinker
			syndrome, fatal familial insomnia)
	464	501939	homo sapiens transcribed sequence with	SEQ ID No: 1168	SEQ ID No: 1169
			strong similarity to protein
			ref: np_057457.1 (h. sapiens) ww
			domain-containing oxidoreductase,
			isoform 1; ww domain-containing
			protein wwox; fragile site fra16d
			oxidoreductase; fragile 16d oxido
			reductase [homo sapiens]
CCL11	465	502658	chemokine (c—c motif) ligand 11	SEQ ID No: 1170	SEQ ID No: 1171	SEQ ID No: 1172
ARHA	466	503820	ras homolog gene family, member a	SEQ ID No: 1173	SEQ ID No: 1174	SEQ ID No: 1175
ETFB	467	504184	electron-transfer-flavoprotein, beta	SEQ ID No: 1176		SEQ ID No: 1177
			polypeptide
ZNF3	468	504811	zinc finger protein 3 (a8-51)	SEQ ID No: 1178		SEQ ID No: 1179
PYGL	469	505573	phosphorylase, glycogen; liver (hers	SEQ ID No: 1180		SEQ ID No: 1181
			disease, glycogen storage disease type
			vi)
PRKCB1	470	50561	protein kinase c, beta 1	SEQ ID No: 1182	SEQ ID No: 1183	SEQ ID No: 1184
FNBP3	471	509515	formin binding protein 3	SEQ ID No: 1185	SEQ ID No: 1186	SEQ ID No: 1187
GNG12	472	509584	guanine nucleotide binding protein (g	SEQ ID No: 1188		SEQ ID No: 1189
			protein), gamma 12
TAF12	473	509588	taf12 rna polymerase ii, tata box	SEQ ID No: 1190	SEQ ID No: 1191	SEQ ID No: 1192
			binding protein (tbp)-associated factor,
			20 kda
RPL27A	474	509719	ribosomal protein l27a	SEQ ID No: 1193	SEQ ID No: 1194	SEQ ID No: 1195
PHB	475	509735	prohibitin	SEQ ID No: 1196	SEQ ID No: 1197	SEQ ID No: 1198
SFRS9	476	509751	splicing factor, arginine/serine-rich 9	SEQ ID No: 1199		SEQ ID No: 1200
NONO	477	509887	non-pou domain containing, octamer-	SEQ ID No: 1201	SEQ ID No: 1202	SEQ ID No: 1203
			binding
CDH17	478	510130	cadherin 17, li cadherin (liver-intestine)	SEQ ID No: 1204	SEQ ID No: 1205	SEQ ID No: 1206
CCT5	479	510161	chaperonin containing tcp1, subunit 5	SEQ ID No: 1207		SEQ ID No: 1208
			(epsilon)
RRM2	480	510231	ribonucleotide reductase m2	SEQ ID No: 1209	SEQ ID No: 1210	SEQ ID No: 1211
			polypeptide
ENO1	481	510235	enolase 1, (alpha)	SEQ ID No: 1212	SEQ ID No: 1213	SEQ ID No: 1214
DKFZP564B1023	482	510354	hypothetical protein dkfzp564b1023	SEQ ID No: 1215	SEQ ID No: 1216	SEQ ID No: 1217
PPEF1	483	51064	protein phosphatase, ef hand calcium-	SEQ ID No: 1218	SEQ ID No: 1219	SEQ ID No: 1220
			binding domain 1
CKB	484	510977	creatine kinase, brain	SEQ ID No: 1221	SEQ ID No: 1222	SEQ ID No: 1223
TM4SF1	485	511778	transmembrane 4 superfamily member 1	SEQ ID No: 1224	SEQ ID No: 1225	SEQ ID No: 1226
UBE2D3	486	512000	ubiquitin-conjugating enzyme e2d 3	SEQ ID No: 1227	SEQ ID No: 1228	SEQ ID No: 1229
			(ubc4/5 homolog, yeast)
MRG2	487	512333	likely ortholog of mouse myeloid	SEQ ID No: 1230
			ecotropic viral integration site-related
			gene 2
AK5	488	512824	adenylate kinase 5	SEQ ID No: 1231		SEQ ID No: 1232
	489	512924		SEQ ID No: 1233	SEQ ID No: 1234
	490	513189		SEQ ID No: 1235
GADD45A	491	52065	growth arrest and dna-damage-	SEQ ID No: 1236		SEQ ID No: 1237
			inducible, alpha
GRIA1	492	52228	glutamate receptor, ionotropic, ampa 1	SEQ ID No: 1238	SEQ ID No: 1239	SEQ ID No: 1240
IDH1	493	525983	isocitrate dehydrogenase 1 (nadp+),	SEQ ID No: 1241	SEQ ID No: 1242	SEQ ID No: 1243
			soluble
	494	526038		SEQ ID No: 1244	SEQ ID No: 1245
PTK2	495	52982	ptk2 protein tyrosine kinase 2	SEQ ID No: 1246	SEQ ID No: 1247	SEQ ID No: 1248
CBR3	496	529844	carbonyl reductase 3	SEQ ID No: 1249	SEQ ID No: 1250	SEQ ID No: 1251
COX7A2	497	529882	cytochrome c oxidase subunit viia	SEQ ID No: 1252	SEQ ID No: 1253	SEQ ID No: 739
			polypeptide 2 (liver)
	498	530034		SEQ ID No: 1254	SEQ ID No: 1255
	499	530037		SEQ ID No: 1256	SEQ ID No: 1257
UBA52	500	530069	ubiquitin a-52 residue ribosomal protein	SEQ ID No: 1258	SEQ ID No: 1259	SEQ ID No: 393
			fusion product 1
COX7C	501	530338	cytochrome c oxidase subunit viic	SEQ ID No: 1260	SEQ ID No: 1261	SEQ ID No: 1262
RPL5	502	530368	ribosomal protein 15	SEQ ID No: 1263	SEQ ID No: 1264	SEQ ID No: 1265
FLIPT1	503	53061	fly-like putative organic ion transporter 1	SEQ ID No: 1266	SEQ ID No: 1267	SEQ ID No: 1268
	504	530744	homo sapiens cyclophilin mrna,	SEQ ID No: 1269	SEQ ID No: 1270
			complete cds
RPL13A	505	530773	ribosomal protein l13a	SEQ ID No: 1271	SEQ ID No: 1272	SEQ ID No: 1273
	506	531366		SEQ ID No: 1274	SEQ ID No: 1275
EPS15R	507	531496	epidermal growth factor receptor	SEQ ID No: 1276	SEQ ID No: 1277	SEQ ID No: 1278
			substrate eps15r
STMN1	508	53227	stathmin 1/oncoprotein 18	SEQ ID No: 1279	SEQ ID No: 1280	SEQ ID No: 1281
MDH1	509	53316	malate dehydrogenase 1, nad (soluble)	SEQ ID No: 1282		SEQ ID No: 1283
	510	53331	loc350717	SEQ ID No: 1284
HCNGP	511	544680	transcriptional regulator protein	SEQ ID No: 1285	SEQ ID No: 1286	SEQ ID No: 1287
	512	544767		SEQ ID No: 1288	SEQ ID No: 1289
	513	544806		SEQ ID No: 1290	SEQ ID No: 1291
TMSB4X	514	544841	thymosin, beta 4, x chromosome	SEQ ID No: 1292	SEQ ID No: 1293	SEQ ID No: 1294
	515	544875		SEQ ID No: 1295	SEQ ID No: 1296
RPL5	516	544885	ribosomal protein l5	SEQ ID No: 1297	SEQ ID No: 1298	SEQ ID No: 1265
	517	545000		SEQ ID No: 1299	SEQ ID No: 1300
	518	545236		SEQ ID No: 1301	SEQ ID No: 1302
LOC92906	519	545423	hypothetical protein bc008217	SEQ ID No: 1303	SEQ ID No: 1304	SEQ ID No: 30
RPL29	520	545580	ribosomal protein l29	SEQ ID No: 1305	SEQ ID No: 1306	SEQ ID No: 1307
TM9SF2	521	546351	transmembrane 9 superfamily member 2	SEQ ID No: 1308		SEQ ID No: 1309
GNB2L1	522	546439	guanine nucleotide binding protein (g	SEQ ID No: 1310	SEQ ID No: 1311	SEQ ID No: 1312
			protein), beta polypeptide 2-like 1
WASF3	523	546460	was protein family, member 3	SEQ ID No: 1313	SEQ ID No: 1314	SEQ ID No: 1315
RAB7	524	546545	rab7, member ras oncogene family	SEQ ID No: 1316	SEQ ID No: 1317	SEQ ID No: 1318
RPS8	525	546664	ribosomal protein s8	SEQ ID No: 1319	SEQ ID No: 1320	SEQ ID No: 1321
	526	546935		SEQ ID No: 1322	SEQ ID No: 1323
	527	547224		SEQ ID No: 1324	SEQ ID No: 1325
	528	547334		SEQ ID No: 1326	SEQ ID No: 1327
WASL	529	547443	wiskott-aldrich syndrome-like	SEQ ID No: 1328		SEQ ID No: 1329
RPL10A	530	548702	ribosomal protein l10a	SEQ ID No: 1330	SEQ ID No: 1331	SEQ ID No: 1332
BOP1	531	548777	block of proliferation 1	SEQ ID No: 1333	SEQ ID No: 1334	SEQ ID No: 1335
G22P1	532	549065	thyroid autoantigen 70 kda (ku antigen)	SEQ ID No: 1336	SEQ ID No: 1337	SEQ ID No: 1338
ARSD	533	549139	arylsulfatase d	SEQ ID No: 1339	SEQ ID No: 1340	SEQ ID No: 1341
RPS8	534	549152	ribosomal protein s8	SEQ ID No: 1342	SEQ ID No: 1343	SEQ ID No: 1321
EIF3S2	535	549173	eukaryotic translation initiation factor 3,	SEQ ID No: 1344	SEQ ID No: 1345	SEQ ID No: 1346
			subunit 2 beta, 36 kda
YWHAQ	536	549178	tyrosine 3-monooxygenase/tryptophan	SEQ ID No: 1347		SEQ ID No: 1348
			5-monooxygenase activation protein,
			theta polypeptide
RPL5	537	549200	ribosomal protein 15	SEQ ID No: 1349	SEQ ID No: 1350	SEQ ID No: 1265
NPM1	538	549212	nucleophosmin (nucleolar		SEQ ID No: 1351	SEQ ID No: 1352
			phosphoprotein b23, numatrin)
COX5B	539	549361	cytochrome c oxidase subunit vb	SEQ ID No: 1353		SEQ ID No: 478
PPP2CA	540	550315	protein phosphatase 2 (formerly 2a),	SEQ ID No: 1354	SEQ ID No: 1355	SEQ ID No: 1066
			catalytic subunit, alpha isoform
MYH1	541	561922	myosin, heavy polypeptide 1, skeletal	SEQ ID No: 1356	SEQ ID No: 1357	SEQ ID No: 1358
			muscle, adult
ACTA1	542	561948	actin, alpha 1, skeletal muscle	SEQ ID No: 1359	SEQ ID No: 1360	SEQ ID No: 1361
TTN	543	562021	titin	SEQ ID No: 1362	SEQ ID No: 1363	SEQ ID No: 1364
XRCC5	544	563112	x-ray repair complementing defective	SEQ ID No: 1365		SEQ ID No: 1366
			repair in chinese hamster cells 5
			(double-strand-break rejoining; ku
			autoantigen, 80 kda)
CCNB1	545	563130	cyclin b1	SEQ ID No: 1367	SEQ ID No: 1368	SEQ ID No: 1369
HSPD1	546	563819	heat shock 60 kda protein 1 (chaperonin)	SEQ ID No: 1370	SEQ ID No: 1371	SEQ ID No: 1372
HMGB1	547	564501	high-mobility group box 1	SEQ ID No: 1373		SEQ ID No: 1374
SP3	548	564535	sp3 transcription factor	SEQ ID No: 1375	SEQ ID No: 1376
GSTT2	549	564547	glutathione s-transferase theta 2	SEQ ID No: 1377	SEQ ID No: 1378	SEQ ID No: 1379
XRCC5	550	587547	x-ray repair complementing defective	SEQ ID No: 1380	SEQ ID No: 1381	SEQ ID No: 1366
			repair in chinese hamster cells 5
			(double-strand-break rejoining; ku
			autoantigen, 80 kda)
CRNKL1	551	590592	crn, crooked neck-like 1 (drosophila)	SEQ ID No: 1382	SEQ ID No: 1383	SEQ ID No: 1384
UBE2C	552	592041	ubiquitin-conjugating enzyme e2c	SEQ ID No: 1385		SEQ ID No: 1386
PPP4R2	553	592521	protein phosphatase 4, regulatory		SEQ ID No: 1387	SEQ ID No: 1388
			subunit 2
PDK4	554	594120	pyruvate dehydrogenase kinase,	SEQ ID No: 1389		SEQ ID No: 1390
			isoenzyme 4
	555	594540	similar to metallothionein-ie (mt-1e)	SEQ ID No: 1391
BPHL	556	595600	biphenyl hydrolase-like (serine	SEQ ID No: 1392	SEQ ID No: 1393	SEQ ID No: 1394
			hydrolase; breast epithelial mucin-
			associated antigen)
ZNF204	557	60204	zinc finger protein 204	SEQ ID No: 1395	SEQ ID No: 1396
HOXA1	558	611075	homeo box a1	SEQ ID No: 1397	SEQ ID No: 1398	SEQ ID No: 1399
C22ORF19	559	611123	chromosome 22 open reading frame 19	SEQ ID No: 1400	SEQ ID No: 1401	SEQ ID No: 1402
MYF6	560	611255	myogenic factor 6 (herculin)	SEQ ID No: 1403	SEQ ID No: 1404	SEQ ID No: 1405
KIAA1181	561	611623	kiaa1181 protein	SEQ ID No: 1406		SEQ ID No: 1407
AMPD1	562	611660	adenosine monophosphate deaminase 1	SEQ ID No: 1408		SEQ ID No: 1409
			(isoform m)
TNNT3	563	611783	troponin t3, skeletal, fast	SEQ ID No: 1410		SEQ ID No: 1411
NEDD5	564	611946	neural precursor cell expressed,	SEQ ID No: 1412	SEQ ID No: 1413	SEQ ID No: 1414
			developmentally down-regulated 5
HSPA9B	565	612365	heat shock 70 kda protein 9b (mortalin-	SEQ ID No: 1415	SEQ ID No: 1416	SEQ ID No: 664
			2)
	566	62429		SEQ ID No: 1417	SEQ ID No: 1418
	567	624513	homo sapiens transcribed sequence with	SEQ ID No: 1419	SEQ ID No: 1420
			strong similarity to protein pir: s29331
			(h. sapiens) s29331 glutamate
			dehydrogenase - human
GNB2L1	568	625541	guanine nucleotide binding protein (g	SEQ ID No: 1421	SEQ ID No: 1422	SEQ ID No: 1312
			protein), beta polypeptide 2-like 1
GNB2L1	569	625574	guanine nucleotide binding protein (g	SEQ ID No: 1423	SEQ ID No: 1424	SEQ ID No: 1312
			protein), beta polypeptide 2-like 1
MYL3	570	628602	myosin, light polypeptide 3, alkali;	SEQ ID No: 1425	SEQ ID No: 1426	SEQ ID No: 1427
			ventricular, skeletal, slow
COX6B	571	632026	cytochrome c oxidase subunit vib	SEQ ID No: 1428	SEQ ID No: 1429	SEQ ID No: 1430
DNAJD1	572	664980	dnaj (hsp40) homolog, subfamily d,	SEQ ID No: 1431		SEQ ID No: 1432
			member 1
AKR1A1	573	665117	aldo-keto reductase family 1, member	SEQ ID No: 1433	SEQ ID No: 1434	SEQ ID No: 1435
			a1 (aldehyde reductase)
MAP2K7	574	665682	mitogen-activated protein kinase kinase 7	SEQ ID No: 1436	SEQ ID No: 1437	SEQ ID No: 1438
SLC7A6	575	665778	solute carrier family 7 (cationic amino	SEQ ID No: 1439	SEQ ID No: 1440	SEQ ID No: 1441
			acid transporter, y+ system), member 6
ANXA6	576	665818	annexin a6	SEQ ID No: 1442	SEQ ID No: 1443	SEQ ID No: 1444
HIST1H4C	577	667303	histone 1, h4c	SEQ ID No: 1445	SEQ ID No: 1446	SEQ ID No: 1447
	578	66800		SEQ ID No: 1448
CPSF5	579	66820	cleavage and polyadenylation specific	SEQ ID No: 1449		SEQ ID No: 1450
			factor 5, 25 kda
	580	66832		SEQ ID No: 1451
	581	66836		SEQ ID No: 1452
GTF2E1	582	668494	general transcription factor iie,	SEQ ID No: 1453	SEQ ID No: 1454	SEQ ID No: 1455
			polypeptide 1, alpha 56 kda
	583	66895	homo sapiens transcribed sequences	SEQ ID No: 1456
RPS14	584	67721	ribosomal protein s14	SEQ ID No: 1457	SEQ ID No: 1458	SEQ ID No: 1459
KRT23	585	67740	keratin 23 (histone deacetylase	SEQ ID No: 1460	SEQ ID No: 1461	SEQ ID No: 1462
			inducible)
	586	67776		SEQ ID No: 1463
	587	68140		SEQ ID No: 1464	SEQ ID No: 1465
	588	68141		SEQ ID No: 1466
FLJ10916	589	68176	hypothetical protein flj10916	SEQ ID No: 1467	SEQ ID No: 1468	SEQ ID No: 1469
ERCC4	590	682268	excision repair cross-complementing	SEQ ID No: 1470	SEQ ID No: 1471	SEQ ID No: 1472
			rodent repair deficiency,
			complementation group 4
	591	68227		SEQ ID No: 1473	SEQ ID No: 1474
COL5A1	592	68276	collagen, type v, alpha 1	SEQ ID No: 1475		SEQ ID No: 1476
MYOM1	593	68351	myomesin 1 (skelemin) 185 kda	SEQ ID No: 1477		SEQ ID No: 1478
NEK6	594	69584	nima (never in mitosis gene a)-related	SEQ ID No: 1479		SEQ ID No: 1480
			kinase 6
RPS23	595	70825	ribosomal protein s23	SEQ ID No: 1481	SEQ ID No: 1482	SEQ ID No: 1483
RPL5	596	71096	ribosomal protein 15	SEQ ID No: 1484	SEQ ID No: 1485	SEQ ID No: 1265
HSF1	597	712675	heat shock transcription factor 1	SEQ ID No: 1486	SEQ ID No: 1487	SEQ ID No: 1488
FRAP1	598	713218	fk506 binding protein 12-rapamycin	SEQ ID No: 1489	SEQ ID No: 1490	SEQ ID No: 1491
			associated protein 1
MGC27165	599	713459	hypothetical protein mgc27165	SEQ ID No: 1492	SEQ ID No: 1493
RPS27	600	72056	ribosomal protein s27	SEQ ID No: 1494	SEQ ID No: 1495	SEQ ID No: 1496
			(metallopanstimulin 1)
RELA	601	723731	v-rel reticuloendotheliosis viral	SEQ ID No: 1497		SEQ ID No: 1498
			oncogene homolog a, nuclear factor of
			kappa light polypeptide gene enhancer
			in b-cells 3, p65 (avian)
RYR3	602	72497	ryanodine receptor 3	SEQ ID No: 1499		SEQ ID No: 1500
COL6A1	603	726342	collagen, type vi, alpha 1	SEQ ID No: 1501	SEQ ID No: 1502	SEQ ID No: 825
CNN1	604	726779	calponin 1, basic, smooth muscle	SEQ ID No: 1503		SEQ ID No: 1504
ITIH1	605	72694	inter-alpha (globulin) inhibitor, h1	SEQ ID No: 1505		SEQ ID No: 1506
			polypeptide
PDE1A	606	727792	phosphodiesterase 1a, calmodulin-	SEQ ID No: 1507	SEQ ID No: 1508	SEQ ID No: 1509
			dependent
SSR2	607	72789	signal sequence receptor, beta	SEQ ID No: 1510	SEQ ID No: 1511	SEQ ID No: 1512
			(translocon-associated protein beta)
NFYA	608	730787	nuclear transcription factor y, alpha	SEQ ID No: 1513	SEQ ID No: 1514	SEQ ID No: 1515
RPS7	609	73590	ribosomal protein s7	SEQ ID No: 1516	SEQ ID No: 1517	SEQ ID No: 1518
	610	74834		SEQ ID No: 1519
SVIL	611	754018	supervillin	SEQ ID No: 1520		SEQ ID No: 1521
THPO	612	754034	thrombopoietin (myeloproliferative	SEQ ID No: 1522	SEQ ID No: 1523	SEQ ID No: 1524
			leukemia virus oncogene ligand,
			megakaryocyte growth and
			development factor)
C1ORF29	613	754479	chromosome 1 open reading frame 29	SEQ ID No: 1525	SEQ ID No: 1526	SEQ ID No: 1527
IFITM1	614	755599	interferon induced transmembrane	SEQ ID No: 1528	SEQ ID No: 1529	SEQ ID No: 1530
			protein 1 (9-27)
RARB	615	755663	retinoic acid receptor, beta	SEQ ID No: 1531	SEQ ID No: 1532	SEQ ID No: 398
BMP6	616	768168	bone morphogenetic protein 6	SEQ ID No: 1533	SEQ ID No: 1534	SEQ ID No: 1535
RPS6KB1	617	773319	ribosomal protein s6 kinase, 70 kda,	SEQ ID No: 1536	SEQ ID No: 1537	SEQ ID No: 1538
			polypeptide 1
R30953_1	618	782601	hypothetical protein r30953_1	SEQ ID No: 1539	SEQ ID No: 1540	SEQ ID No: 1541
RNF13	619	785886	ring finger protein 13	SEQ ID No: 1542	SEQ ID No: 1543	SEQ ID No: 1544
CGI-128	620	786662	cgi-128 protein	SEQ ID No: 1545	SEQ ID No: 1546	SEQ ID No: 1547
	621	78879	similar to complement component 3	SEQ ID No: 1548
CDH1	622	79598	cadherin 1, type 1, e-cadherin	SEQ ID No: 1549	SEQ ID No: 1550	SEQ ID No: 1551
			(epithelial)
FHL3	623	796475	four and a half lim domains 3	SEQ ID No: 1552	SEQ ID No: 1553	SEQ ID No: 1554
	624	79829	homo sapiens transcribed sequences	SEQ ID No: 1555
VAV1	625	80384	vav 1 oncogene	SEQ ID No: 1556	SEQ ID No: 1557	SEQ ID No: 1558
PPP1R14A	626	809611	protein phosphatase 1, regulatory	SEQ ID No: 1559		SEQ ID No: 1560
			(inhibitor) subunit 14a
ETV4	627	809959	ets variant gene 4 (e1a enhancer	SEQ ID No: 1561	SEQ ID No: 1562	SEQ ID No: 1563
			binding protein, e1af)
S100A2	628	810813	s100 calcium binding protein a2	SEQ ID No: 1564	SEQ ID No: 1565	SEQ ID No: 1566
ITGA2	629	811740	integrin, alpha 2 (cd49b, alpha 2	SEQ ID No: 1567	SEQ ID No: 1568	SEQ ID No: 1569
			subunit of vla-2 receptor)
YWHAZ	630	811939	tyrosine 3-monooxygenase/tryptophan	SEQ ID No: 1570	SEQ ID No: 1571	SEQ ID No: 1572
			5-monooxygenase activation protein,
			zeta polypeptide
PCDH7	631	813384	bh-protocadherin (brain-heart)	SEQ ID No: 1573		SEQ ID No: 1574
	632	813755	similar to zinc finger protein 7 (zinc	SEQ ID No: 1575	SEQ ID No: 1576
			finger protein kox4) (zinc finger protein
			hf. 16)
GJB2	633	823859	gap junction protein, beta 2, 26 kda	SEQ ID No: 1577	SEQ ID No: 1578	SEQ ID No: 1579
			(connexin 26)
VWF	634	840486	von willebrand factor	SEQ ID No: 1580	SEQ ID No: 1581	SEQ ID No: 1582
NME1	635	845363	non-metastatic cells 1, protein (nm23a)	SEQ ID No: 1583		SEQ ID No: 288
			expressed in
EIF3S6	636	856961	eukaryotic translation initiation factor 3,	SEQ ID No: 1584		SEQ ID No: 1585
			subunit 6 48 kda
	637	86078		SEQ ID No: 1586
	638	869440		SEQ ID No: 1587
RPL30	639	878681	ribosomal protein 130	SEQ ID No: 1588		SEQ ID No: 1589
B2M	640	878798	beta-2-microglobulin	SEQ ID No: 1590		SEQ ID No: 813
HMGB2	641	884365	high-mobility group box 2	SEQ ID No: 1591		SEQ ID No: 552
LAMR1	642	884644	laminin receptor 1 (ribosomal protein	SEQ ID No: 1592		SEQ ID No: 987
			sa, 67 kda)
PRAME	643	897956	preferentially expressed antigen in	SEQ ID No: 1593		SEQ ID No: 1594
			melanoma
NME2	644	951066	non-metastatic cells 2, protein (nm23b)	SEQ ID No: 1595		SEQ ID No: 1596
			expressed in

Table 1 above identifies a library of polynucleotide sequences of SEQ ID NO. 1 to SEQ ID NO. 1556 and arranges them into sets. Table 1 indicates, wherever available, the name of the gene with its gene symbol, its Image Clone and, for each gene, the relevant SEQ ID NOS defining the set. The “3′” and “5′” columns represent ESTs and the “Ref.” column represent mRNAs of the named gene or Image Clone.

Thus, the nucleotide sequences of the present invention can be defined by the differents sets, but can also be defined by the name of the gene or fragments thereof as recited in Table 1. Each polynucleotide sequence in Table 1 can therefore be considered as a marker of the corresponding gene. Each marker corresponds to a gene in the human genome; i.e., such marker is identifiable as all or a portion of a gene. The term “marker”, as used herein, is thus meant to refer to the complete gene nucleotide sequence or an EST nucleotide sequence derived from that gene (or a subsequence or complement thereof), the expression or level of which changes with certain conditions, disorders or diseases. Where the expression of the gene correlates with a certain condition, disorder or disease, the gene is a marker for that condition, disorder or disease. Any RNA transcribed from a marker gene (e.g., mRNAs), any cDNA or cRNA produced therefrom, and any nucleic acid derived therefrom, such as synthetic nucleic acid having a sequence derived from the gene corresponding to the marker gene, are also encompassed by the present invention.

Each mRNA sequence in the Ref. column represents one of the various mRNA splice forms of the gene that are known in the art; e.g., splice forms described in publicly available genomic databases. A skilled artisan is able to select, by routine experimentation, one or more appropriate splice form(s) by, e.g., determining those splice forms having a sequence that matches the sequence of the corresponding Image Clone with a predetermined level of homology.

A disease, disorder, or condition “associated with” an aberrant expression of a nucleic acid refers to a disease, disorder, or condition in a subject which is caused by, contributed to by, or causative of an aberrant level of expression of a nucleic acid.

By “nucleic acids,” as used herein, is meant polynucleotides, e.g., isolated, such as isolated deoxyribonucleic acid (DNA), and, where appropriate, isolated ribonucleic acid (RNA). The term is also understood to include, as equivalents, analogs of RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single (sense or antisense) and double-stranded polynucleotides. ESTs, chromosomes or genomic DNA, cDNAs, mRNAs, and rRNAs are representative examples of molecules that can be referred to as nucleic acids. DNA can be obtained from said nucleic acids sample and RNA can be obtained by transcription of said DNA. In addition, mRNA can be isolated from said nucleic acids sample and cDNA can be obtained by reverse transcription of said mRNA.

The term “subsequence”, as used herein, is meant to refer to any sequence corresponding to a part of said polynucleotide sequence, which would also be suitable to perform the method of analysis according to the invention. A person skilled in the art can choose the position and length of a subsequence of the invention by applying routine experiments. A subsequence can have at least about 80% homology with said polynucleotide sequence; e.g., at least about 85%, at least about 90%, at least about 95%, or at least about 99% homology.

The term “pool”, as used herein, is meant to refer to a group of nucleic acid sequences comprising one or more sequences, for example about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500,1600, 1700, 1800, 1900, or 2000 sequences.

The number of sets may vary in the range of from 1 to the maximum number of sets described therein, e.g., 646 sets, for example about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 550, or 600 sets.

The over or under expression (or respectively “up regulation” and “down regulation,” which may be used interchangeably with over or under expression, respectively) can be determined by any known method within the skill in the art, such as disclosed in PCT patent application WO 02/103320, the entire disclosure of which is herein incorporated by reference. Such methods can comprise the detection of difference in the expression of the polynucleotide sequences according to the present invention in relation to at least one control. Said control can comprise, for example, polynucleotide sequence(s) from sample of the same patient or from a pool of patients exhibiting histopathologic features of colorectal disease, or selected from among reference sequence(s) which are already known to be over or under expressed. The expression level of said control can be an average or an absolute value of the expression of reference polynucleotide sequences. These values can be processed (e.g., statistically) in order to accentuate the difference relative to the expression of the polynucleotide sequences of the invention.

The analysis of the over or under expression of polynucleotide sequences can be carried out on sample, such as biological material derived from any mammalian cells, including cell lines, xenografts, and human tissues, preferably from colon tissue. The method according to the invention can be performed on sample from a human subject or an animal (for example for veterinary application or preclinical trial).

By “over or underexpression” of a polynucleotide sequence, as used herein, is meant that overexpression of certain sequences is detected simultaneously with the underexpression of other sequences. “Simultaneously” means concurrent with or within a biologic or functionally relevant period of time during which the over expression of a sequence can be followed by the under expression of another sequence, or conversely, e.g., because both over and under expression are directly or indirectly correlated.

In one embodiment, the method according to the present invention is therefore directed to the analysis of differential gene expression associated with colon tumors wherein the pool of polynucleotide sequences corresponds to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

1; 4; 9; 10; 11; 13; 15; 16; 17; 18; 21; 27; 28; 30; 31; 34; 37; 39; 41; 43; 45; 46; 52; 53; 58; 59; 60; 65; 68; 69; 70; 75; 76; 78; 79; 80; 84; 85; 87; 88; 90; 95; 96; 98; 99; 101; 105; 108; 110; 111; 113; 114; 116; 119; 120; 122; 124; 125; 126; 127; 130; 131; 138; 139; 140; 141; 143; 150; 152; 153; 155; 159; 164; 171; 175; 176; 178; 181; 182; 184; 185; 189; 192; 196; 197; 198; 203; 205; 207; 208; 210; 213; 214; 215; 216; 218; 221; 223; 225; 227; 231; 235; 241; 243; 251; 256; 259; 261; 262; 263; 264; 266; 267; 268; 270; 279; 281; 286; 287; 288; 291; 298; 299; 301; 307; 310; 312; 313; 317; 319; 329; 331; 332; 337; 338; 339; 340; 341; 342; 344; 346; 352; 354; 357; 360; 361; 366; 368; 369; 377; 379; 381; 384; 385; 386; 390; 392; 394; 395; 397; 398; 400; 401; 405; 406; 409; 410; 413; 423; 427; 434; 436; 437; 438; 440; 442; 443; 444; 445; 448; 454; 459; 463; 464; 467; 469; 470; 488; 492; 495; 500; 503; 507; 508; 516; 518; 520; 522; 524; 538; 543; 547; 549; 552; 555; 557; 561; 567; 568; 569; 573; 574; 583; 586; 588; 592; 596; 597; 598; 599; 600; 601; 604; 609; 610; 611; 614; 616; 617; 621; 626; 627; 629; 630; 631; 632; 634; 635; 636; 638; 641; 642; and 644.

Said analysis can comprise at least one of the following steps:

• • The detection of the overexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequences sets consisting of sets:

1; 9; 10; 16; 18; 27; 28; 30; 39; 41; 43; 45; 53; 58; 60; 65; 69; 75; 76; 113; 116; 120; 122; 126; 127; 130; 131; 138; 139; 140; 141; 143; 150; 152; 153; 159; 181; 182; 184; 189; 192; 197; 198; 210; 213; 214; 216; 218; 225; 227; 243; 259; 261; 264; 266; 267; 268; 281; 286; 287; 288; 291; 299; 307; 312; 313; 317; 319; 332; 337; 338; 339; 340; 341; 342; 344; 354; 357; 360; 361; 368; 381; 384; 385; 392; 394; 397; 398; 405; 423; 427; 442; 444; 464; 467; 469; 488; 495; 500; 507; 508; 516; 520; 522; 524; 538; 543; 547; 549; 552; 561; 567; 568; 569; 573; 586; 588; 592; 596; 600; 609; 614; 627; 629; 630; 635; 636; 641; 642; and 644.

• • The detection of the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

4; 11; 13; 15; 17; 21; 31; 34; 37; 46; 52; 59; 68; 70; 78; 79; 80; 84; 85; 87; 88; 90; 95; 96; 98; 99; 101; 105; 108; 110; 111; 114; 119; 124; 125; 155; 164; 171; 175; 176; 178; 185; 196; 203; 205; 207; 208; 215; 221; 223; 231; 235; 241; 251; 256; 262; 263; 270; 279; 298; 301; 310; 329; 331; 346; 352; 366; 369; 377; 379; 386; 390; 395; 400; 401; 406; 409; 410; 413; 434; 436; 437; 438; 440; 443; 445; 448; 454; 459; 463; 470; 492; 503; 518; 555; 557; 574; 583; 597; 598; 599; 601; 604; 610; 611; 616; 617; 621; 626; 631; 632; 634; and 638.

In a preferred embodiment, the sets for analyzing differential gene expression associated with colon tumors can, for example, consist of those mentioned in Table 2:

TABLE 2
	Clone
	identifier		Gene	Reference	Title of cluster
Sets	(Image)	Cluster (Unigene)	Symbol	sequences	(Gene name)	SEQ ID Numbers
1	1012666	ughs.82422:175	capg	nm_001747	capping protein (actin filament),	SEQ ID NO: 1597
					gelsolin-like
4	1046837	ughs.235935:175	nov	nm_002514	nephroblastoma overexpressed gene	SEQ ID NO: 1598
15	110486	ughs.404336:175	loc92906	nm_138394	hypothetical protein bc008217	SEQ ID NO: 1599
21	117240	ughs.180398:175	lpp	nm_005578	lim domain containing preferred	SEQ ID NO: 1600
					translocation partner in lipoma
27	119530	ughs.17287:175	kcnj15	nm_002243,	potassium inwardly-rectifying	SEQ ID NO: 1601
				nm_170736,	channel, subfamily j, member 15	SEQ ID NO: 1602
				nm_170737		SEQ ID NO: 1603
58	1338831
68	139789	ughs.79095:175	eps15	nm_001981	epidermal growth factor receptor	SEQ ID NO: 1604
					pathway substrate 15
75	1456160	ughs.531989:175	azgp1	nm_001185	alpha-2-glycoprotein 1, zinc	SEQ ID NO: 1605
79	146922
95	153461	ughs.25511:175	tgfb1i1	nm_015927	transforming growth factor beta 1	SEQ ID NO: 1606
					induced transcript 1
98	153854	ughs.279604:175	des	nm_001927	desmin	SEQ ID NO: 1607
101	154600	ughs.80776:175	plcd1	nm_006225	phospholipase c, delta 1	SEQ ID NO: 1608
114	1667886	ughs.75486:175	hsf4	nm_001538	heat shock transcription factor 4	SEQ ID NO: 1609
119	1731982	ughs.271620:175	plcg2	nm_002661	phospholipase c, gamma 2	SEQ ID NO: 1610
					(phosphatidylinositol-specific)
127	186331	ughs.32393:175	dars	nm_001349	aspartyl-trna synthetase	SEQ ID NO: 1611
131	1912132	ughs.250822:175	stk6	nm_003600,	serine/threonine kinase 6	SEQ ID NO: 1612
				nm_198433,		SEQ ID NO: 1613
				nm_198434,		SEQ ID NO: 1614
				nm_198435,		SEQ ID NO: 1615
				nm_198436,		SEQ ID NO: 1616
				nm_198437		SEQ ID NO: 1617
140	195702	ughs.270920:175	dap3	nm_004632,	death associated protein 3	SEQ ID NO: 1618
				nm_033657		SEQ ID NO: 1619
155	2055272	ughs.252938:175	lrp2	nm_004525	low density lipoprotein-related	SEQ ID NO: 1620
					protein 2
176	2349125	ughs.136713:175	vpreb3	nm_013378	pre-b lymphocyte gene 3	SEQ ID NO: 1621
192	241788	ughs.300774:175	fgb	nm_005141	fibrinogen, b beta polypeptide	SEQ ID NO: 1622
241	272189	ughs.260523:175	nras	nm_002524	neuroblastoma ras viral (v-ras)	SEQ ID NO: 1623
					oncogene homolog
243	272502	ughs.374334:175	cct4	nm_006430	chaperonin containing tcp1, subunit 4	SEQ ID NO: 1624
					(delta)
259	285780	ughs.2936:175	mmp13	nm_002427	matrix metalloproteinase 13	SEQ ID NO: 1625
					(collagenase 3)
263	288874	ughs.37014:175;	ca7;	nm_005182;	carbonic anhydrase vii; zinc finger	SEQ ID NO: 1626
		ughs.48589:175	znf228	nm_013380	protein 228	SEQ ID NO: 1627
270	30066	ughs.89657:175	ilk	nm_004517	integrin-linked kinase	SEQ ID NO: 1628
279	306697	ughs.82508:175	thap11	nm_020457	thap domain containing 11	SEQ ID NO: 1629
286	310860	ughs.368481:175	nudt5	nm_014142	nudix (nucleoside diphosphate linked	SEQ ID NO: 1630
					moiety x)-type motif 5
298	322452	ughs.124411:175	chga	nm_001275	chromogranin a (parathyroid	SEQ ID NO: 1631
					secretory protein 1)
299	322471	ughs.1063:175	snrpc	nm_003093	small nuclear ribonucleoprotein	SEQ ID NO: 1632
					polypeptide c
307	323948	ughs.2316:175	sox9	nm_000346	sry (sex determining region y)-box 9	SEQ ID NO: 1633
					(campomelic dysplasia, autosomal
					sex-reversal)
310	324369	ughs.513557:175	ctbs	nm_004388	chitobiase, di-n-acetyl-	SEQ ID NO: 1634
312	324757	ughs.370504:175	rps15a	nm_001019	ribosomal protein s15a	SEQ ID NO: 1635
313	324930	ughs.28491:175	sat	nm_002970	spermidine/spermine n1-	SEQ ID NO: 1636
					acetyltransferase
317	327684	ughs.148090:175	cdh15	nm_004933	cadherin 15, m-cadherin (myotubule)	SEQ ID NO: 1637
329	342054	ughs.20136:175	cxorf6	nm_005491	chromosome x open reading frame 6	SEQ ID NO: 1638
346	34888	ughs.489521:175;	reln;	nm_005045,	reelin; transcribed locus	SEQ ID NO: 1639
		ughs.492257:175		nm_173054;		SEQ ID NO: 1640
357	358117	ughs.2316:175	sox9	nm_000346	sry (sex determining region y)-box 9
					(campomelic dysplasia, autosomal
					sex-reversal)
360	358683	ughs.133892:175	tpm1	nm_000366	tropomyosin 1 (alpha)	SEQ ID NO: 1641
361	358943	ughs.438837:175	n2n	nm_203458	similar to notch2 protein	SEQ ID NO: 1642
394	383433	ughs.356261:175			similar to laminin receptor 1
395	39593	ughs.12409:175	sst	nm_001048	somatostatin	SEQ ID NO: 1643
398	39972	ughs.432317:175	adam23	nm_003812	a disintegrin and metalloproteinase	SEQ ID NO: 1644
					domain 23
405	415389	ughs.334612:175	snrpe	nm_003094	small nuclear ribonucleoprotein	SEQ ID NO: 1645
					polypeptide e
406	416060	ughs.440934:175	arg1	nm_000045	arginase, liver	SEQ ID NO: 1646
413	427858	ughs.508411:175	gpc6	nm_005708	glypican 6	SEQ ID NO: 1647
427	44152	ughs.1708:175	cct3	nm_005998	chaperonin containing tcp1, subunit 3	SEQ ID NO: 1648
					(gamma)
436	470122	ughs.93841:175	kcnmb1	nm_004137	potassium large conductance	SEQ ID NO: 1649
					calcium-activated channel, subfamily
					m, beta member 1
437	470175	ughs.3548:175	mtcp1	nm_014221	mature t-cell proliferation 1	SEQ ID NO: 1650
438	470279	ughs.408730:175	cntnap1	nm_003632	contactin associated protein 1	SEQ ID NO: 1651
443	47986	ughs.149609:175	itga5	nm_002205	integrin, alpha 5 (fibronectin	SEQ ID NO: 1652
					receptor, alpha polypeptide)
454	488526	ughs.78344:175	myh11	nm_002474,	myosin, heavy polypeptide 11,	SEQ ID NO: 1653
				nm_022844	smooth muscle	SEQ ID NO: 1654
464	501939	ughs.21635:175;	tubg1;	nm_001070;	tubulin, gamma 1; ww domain	SEQ ID NO: 1655
		ughs.461453:175	wwox	nm_016373,	containing oxidoreductase	SEQ ID NO: 1656
				nm_018560,		SEQ ID NO: 1657
				nm_130788,		SEQ ID NO: 1658
				nm_130790,		SEQ ID NO: 1659
				nm_130791,		SEQ ID NO: 1660
				nm_130792,		SEQ ID NO: 1661
				nm_130844		SEQ ID NO: 1662
507	531496	ughs.292072:175	eps15l1	nm_021235	epidermal growth factor receptor	SEQ ID NO: 1663
					pathway substrate 15-like 1
522	546439	ughs.5662:175	gnb2l1	nm_006098	guanine nucleotide binding protein (g	SEQ ID NO: 1664
					protein), beta polypeptide 2-like 1
547	564501	ughs.434102:175	hmgb1	nm_002128	high-mobility group box 1	SEQ ID NO: 1665
552	592041	ughs.93002:175	ube2c	nm_007019,	ubiquitin-conjugating enzyme e2c	SEQ ID NO: 1666
				nm_181799,		SEQ ID NO: 1667
				nm_181800,		SEQ ID NO: 1668
				nm_181801,		SEQ ID NO: 1669
				nm_181802,		SEQ ID NO: 1670
				nm_181803		SEQ ID NO: 1671
555	594540	ughs.454253:175	ptch	nm_000264	patched homolog (drosophila)	SEQ ID NO: 1672
568	625541	ughs.5662:175	gnb2l1	nm_006098	guanine nucleotide binding protein (g
					protein), beta polypeptide 2-like 1
569	625574	ughs.5662:175	gnb2l1	nm_006098	guanine nucleotide binding protein (g
					protein), beta polypeptide 2-like 1
614	755599	ughs.458414:175	ifitm1	nm_003641	interferon induced transmembrane	SEQ ID NO: 1673
					protein 1 (9-27)
631	813384	ughs.443020:175	pcdh7	nm_002589,	bh-protocadherin (brain-heart)	SEQ ID NO: 1674
				nm_032456,		SEQ ID NO: 1675
				nm_032457		SEQ ID NO: 1676
634	840486	ughs.440848:175	vwf	nm_000552	von willebrand factor	SEQ ID NO: 1677
636	856961	ughs.405590:175	eif3s6	nm_001568	eukaryotic translation initiation	SEQ ID NO: 1678
					factor 3, subunit 6 48 kda
641	884365	ughs.434953:175	hmgb2	nm_002129	high-mobility group box 2	SEQ ID NO: 1679
644	951066	ughs.433416:175	nme2	nm_002512	non-metastatic cells 2, protein	SEQ ID NO: 1680
					(nm23b) expressed in

In another embodiment, the method according to the present invention is directed to the analysis of differential gene expression associated with secondary metastatic events in patients with colorectal tumors, in particular visceral metastasis or lymph node metastasis. In the visceral metastasis embodiment, said analysis comprises the detection of the overexpression or the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

2; 3; 10; 22; 24; 25; 30; 32; 33; 35; 36; 39; 40; 41; 42; 47; 50; 54; 57; 67; 72; 86; 97; 102; 103; 104; 107; 117; 118; 120; 128; 130; 132; 133; 134; 137; 144; 145; 146; 147; 149; 153; 156; 158; 162; 163; 165; 169; 170; 173; 174; 179; 180; 188; 191; 193; 194; 195; 199; 200; 201; 202; 204; 206; 209; 210; 211; 212; 213; 214; 216; 217; 219; 222; 234; 238; 246; 248; 249; 250; 255; 271; 272; 273; 276; 277; 278; 282; 283; 284; 291; 292; 293; 294; 295; 296; 303; 304; 305; 306; 308; 312; 314; 318; 323; 324; 325; 326; 330; 336; 337; 338; 339; 340; 341; 342; 343; 344; 347; 349; 350; 351; 353; 356; 359; 360; 361; 362; 363; 364; 371; 372; 374; 378; 380; 381; 382; 383; 384; 387; 388; 393; 396; 397; 399; 402; 403; 408; 414; 415; 417; 418; 419; 420; 421; 422; 426; 428; 430; 432; 433; 441; 446; 449; 457; 458; 460; 465; 471; 472; 473; 475; 476; 478; 480; 481; 482; 484; 485; 486; 490; 493; 494; 497; 501; 502; 504; 505; 509; 510; 514; 516; 520; 525; 526; 527; 528; 529; 530; 537; 538; 539; 541; 545; 546; 550; 558; 559; 560; 561; 562; 564; 565; 566; 571; 576; 577; 578; 580; 581; 584; 585; 586; 590; 591; 593; 594; 595; 596; 602; 607; 609; 612; 613; 615; 623; 624; 625; 633; 635; 639; 640; 643; and 644.

The analysis can comprise at least one of the following steps:

• • The detection of the overexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complement thereof selected from each of predefined polynucleotide sequence sets consisting of sets:

36; 86; 104; 107; 117; 132; 144; 153; 156; 174; 191; 209; 248; 349; 350; 396; 417; 419; 432; 558; 566; 613; 623; 625; 633; and 643.

• • The detection of the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected in each of predefined polynucleotide sequence sets consisting of sets:

2; 3; 10; 22; 24; 25; 30; 32; 33; 35; 39; 40; 41; 42; 47; 50; 54; 57; 67; 72; 97; 102; 103; 118; 120; 128; 130; 133; 134; 137; 145; 146; 147; 149; 158; 162; 163; 165; 169; 170; 173; 179; 180; 188; 193; 194; 195; 199; 200; 201; 202; 204; 206; 210; 211; 212; 213; 214; 216; 217; 219; 222; 234; 238; 246; 249; 250; 255; 271; 272; 273; 276; 277; 278; 282; 283; 284; 291; 292; 293; 294; 295; 296; 303; 304; 305; 306; 308; 312; 314; 318; 323; 324; 325; 326; 330; 336; 337; 338; 339; 340; 341; 342; 343; 344; 347; 351; 353; 356; 359; 360; 361; 362; 363; 364; 371; 372; 374; 378; 380; 381; 382; 383; 384; 387; 388; 393; 397; 399; 402; 403; 408; 414; 415; 418; 420; 421; 422; 426; 428; 430; 433; 441; 446; 449; 457; 458; 460; 465; 471; 472; 473; 475; 476; 478; 480; 481; 482; 484; 485; 486; 490; 493; 494; 497; 501; 502; 504; 505; 509; 510; 514; 516; 520; 525; 526; 527; 528; 529; 530; 537; 538; 539; 541; 545; 546; 550; 559; 560; 561; 562; 564; 565; 571; 576; 577; 578; 580; 581; 584; 585; 586; 590; 591; 593; 594; 595; 596; 602; 607; 609; 612; 615; 624; 635; 639; 640; and 644.

In a preferred embodiment, the sets for analyzing differential gene expression associated with visceral metastasis can, for example, consist of those mentioned in Table 3:

TABLE 3
	Clone		Gene	Reference
Set	identifier	cluster	Symbol	sequences	Title of cluster	SEQ ID Numbers
32	image: 121076	ughs.107476:175;	atp5l;	nm_006476;	atp synthase, h+ transporting,	SEQ ID NO: 1681
		ughs.75275:175	ube4a	nm_004788	mitochondrial f0 complex, subunit g;	SEQ ID NO: 1682
					ubiquitination factor e4a (ufd2
					homolog, yeast)
33	image: 121265	ughs.181315:175	Ifnar1	nm_000629	interferon (alpha, beta and omega)	SEQ ID NO: 1683
					receptor 1
50	image: 129146	ughs.423404:175	cox7a2l	nm_004718	cytochrome c oxidase subunit viia	SEQ ID NO: 1684
					polypeptide 2 like
133	image: 191714	ughs.370504:175;	rps15a;	nm_001019;	ribosomal protein s15a; transcribed
		ughs.486908:175			locus, moderately similar to
					xp_212877.2 ribosomal protein s15a
					[rattus norvegicus]
188	image: 240753
217	image: 258313	ughs.432170:175	cox7b	nm_001866	cytochrome c oxidase subunit viib	SEQ ID NO: 1685
271	image: 301119	ughs.80691:175	ckmt2	nm_001825	creatine kinase, mitochondrial 2	SEQ ID NO: 1686
					(sarcomeric)
284	image: 31027	ughs.180414:175;	hspa8;	nm_006597,	heat shock 70 kda protein 8; fragile x	SEQ ID NO: 1687
		ughs.52788:175	fxr2	nm_153201;	mental retardation, autosomal	SEQ ID NO: 1688
				nm_004860	homolog 2	SEQ ID NO: 1689
296	image: 321973	ughs.108957:175	rps27l	nm_015920	ribosomal protein s27-like	SEQ ID NO: 1690
303	image: 323681	ughs.11156:175	loc51255	nm_016494	hypothetical protein loc51255	SEQ ID NO: 1691
312	image: 324757	ughs.370504:175	rps15a	nm_001019	ribosomal protein s15a
323	image: 33794	ughs.155433:175	atp5c1	nm_001001973,	atp synthase, h+ transporting,	SEQ ID NO: 1692
				nm_005174	mitochondrial f1 complex, gamma	SEQ ID NO: 1693
					polypeptide 1
340	image: 345694	ughs.156316:175	Dcn	nm_001920,	decorin	SEQ ID NO: 1694
				nm_133503,		SEQ ID NO: 1695
				nm_133504,		SEQ ID NO: 1696
				nm_133505,		SEQ ID NO: 1697
				nm_133506,		SEQ ID NO: 1698
				nm_133507		SEQ ID NO: 1699
343	image: 346269	ughs.420269:175	col6a2	nm_001849,	collagen, type vi, alpha 2	SEQ ID NO: 1700
				nm_058174,		SEQ ID NO: 1701
				nm_058175		SEQ ID NO: 1702
361	image: 358943	ughs.438837:175	n2n	nm_203458	similar to notch2 protein	SEQ ID NO: 1703
403	image: 41411	ughs.184582:175;	rpl24;	nm_000986;	ribosomal protein l24; transcribed	SEQ ID NO: 1704
		ughs.206520:175			locus
408	image: 416946	ughs.395309:175	Txn	nm_003329	thioredoxin	SEQ ID NO: 1705
473	image: 509588	ughs.421646:175	taf12	nm_005644	taf12 rna polymerase ii, tata box	SEQ ID NO: 1706
					binding protein (tbp)-associated
					factor, 20 kda
484	image: 510977	ughs.173724:175	Ckb	nm_001823	creatine kinase, brain	SEQ ID NO: 1707
494	image: 526038	ughs.536668:175			transcribed locus
502	image: 530368	ughs.469653:175	rpl5	nm_000969	ribosomal protein l5	SEQ ID NO: 1708
516	image: 544885	ughs.469653:175	rpl5	nm_000969	ribosomal protein l5	SEQ ID NO: 1708
624	image: 79829	ughs.7888:175	erbb4	nm_005235	v-erb-a erythroblastic leukemia viral	SEQ ID NO: 1709
					oncogene homolog 4 (avian)

According to the lymph node metastasis embodiment, said analysis comprises the detection of the overexpression or the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

38; 55; 66; 91; 93; 102; 103; 133; 142; 144; 153; 163; 190; 210; 232; 254; 280; 296; 300; 304; 311; 321; 335; 378; 383; 384; 420; 425; 429; 432; 468; 473; 487; 516; 519; 544; 553; 573; 577; 578; 585; 587; 589; 592; 605; 608; and 644; preferably from sets 142; 144; 153; 190; 280; 468; 519; 553; and 589.

The analysis can comprise at least one of the following steps:

• • The detection of the overexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof selected from each of predefined polynucleotide sequence sets consisting of sets:

55; 66; 144; 153; 432; 553; and 608; preferably 144; 153; and 553.

• • The detection of the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

38; 91; 93; 102; 103; 133; 142; 163; 190; 210; 232; 254; 280; 296; 300; 304; 311; 321; 335; 378; 383; 384; 420; 425; 429; 468; 473; 487; 516; 519; 544; 573; 577; 578; 585; 587; 589; 592; 605; and 644, preferably 142; 190; 280; 468; 519; and 589.

In a further preferred embodiment, the sets for analyzing differential gene expression associated with lymph node metastasis can, for example, consist of those mentioned in Table 4:

TABLE 4
	Clone		Gene	Reference
Set	identifier	Cluster	Symbol	sequences	Title of cluster	SEQ ID Numbers
142	Image: 198903	ughs.418533:175	bub3	nm_004725	bub3 budding uninhibited by	SEQ ID NO: 1710
					benzimidazoles 3 homolog (yeast)
144	Image: 200521	ughs.442936:175	oas1	nm_002534,	2′,5′-oligoadenylate synthetase 1,	SEQ ID NO: 1711
				nm_016816	40/46 kda	SEQ ID NO: 1712
153	Image: 2048801	ughs.439109:175	ntrk2	nm_006180	neurotrophic tyrosine kinase,	SEQ ID NO: 1713
					receptor, type 2
190	Image: 241151	ughs.432424:175	tpp2	nm_003291	tripeptidyl peptidase ii	SEQ ID NO: 1714
280	Image: 307094	ughs.54609:175	gcat	nm_014291	glycine c-acetyltransferase (2-amino-	SEQ ID NO: 1715
					3-ketobutyrate coenzyme a ligase)
468	Image: 504811	ughs.20082:175	znf38	nm_017715,	zinc finger protein 38	SEQ ID NO: 1716
				nm_145914		SEQ ID NO: 1717
553	Image: 592521	ughs.446590:175;	ppp4r2;	nm_174907;	protein phosphatase 4, regulatory	SEQ ID NO: 1718
		ughs.534524:175	flj10213	nm_018029	subunit 2; hypothetical protein	SEQ ID NO: 1719
					flj10213
589	Image: 68176	ughs.179203:175	flj10916	nm_018271	hypothetical protein flj10916	SEQ ID NO: 1720

In a further embodiment, the method of the present invention is directed to the analysis of differential gene expression associated with MSI phenotype in colon cancer. In this embodiment, said analysis comprises the detection of the overexpression or the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

29; 48; 56; 62; 71; 77; 82; 109; 112; 135; 136; 154; 157; 166; 167; 186; 220; 226; 236; 237; 239; 240; 242; 244; 253; 260; 277; 290; 297; 348; 358; 375; 376; 404; 407; 412; 416; 424; 431; 450; 451; 452; 462; 474; 477; 479; 486; 498; 511; 521; 533; 534; 535; 542; 572; 619; and 622.

The analysis can comprise at least one of the following steps:

• • The detection of the overexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof selected from each of predefined polynucleotide sequence sets consisting of sets:

48; 56; 62; 157; 186; 220; 226; 253; 260; 376; 450; 452; 462; 498; and 511.

• • The detection of the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

29; 71; 77; 82; 109; 112; 135; 136; 154; 166; 167; 236; 237; 239; 240; 242; 244; 277; 290; 297; 348; 358; 375; 404; 407; 412; 416; 424; 431; 451; 474; 477; 479; 486; 521; 533; 534; 535; 542; 572; 619; and 622.

In a preferred embodiment, the sets for analyzing differential gene expression associated with MSI phenotype can, for example, consist of those mentioned in Table 5:

TABLE 5
	Clone		Gene	Reference
Set	identifier	Cluster	Symbol	sequences	Title of cluster	SEQ ID Numbers
29	Image: 120009	Ughs.77578:175	usp9x	nm_004652,	ubiquitin specific protease 9, x-	SEQ ID NO: 1721
				nm_021906	linked (fat facets-like, drosophila)	SEQ ID NO: 1722
62	image: 136361	Ughs.519034:175;	tnfsf13	nm_003808,	transcribed locus; tumor necrosis	SEQ ID NO: 1723
		ughs.54673:175		nm_003809,	factor (ligand) superfamily, member	SEQ ID NO: 1724
				nm_153012,	12	SEQ ID NO: 1725
				nm_172087,		SEQ ID NO: 1726
				nm_172088,		SEQ ID NO: 1727
				nm_172089		SEQ ID NO: 1728
71	image: 143519	Ughs.227729:175	fkbp2	nm_004470,	fk506 binding protein 2, 13 kda	SEQ ID NO: 1729
				nm_057092		SEQ ID NO: 1730
109	image: 159885	Ughs.298469:175	ace	nm_000789,	angiotensin i converting enzyme	SEQ ID NO: 1731
				nm_152830,	(peptidyl-dipeptidase a) 1	SEQ ID NO: 1732
				nm_152831		SEQ ID NO: 1733
136	image: 192581	Ughs.437040:175	ptpn21	nm_007039	protein tyrosine phosphatase, non-	SEQ ID NO: 1734
					receptor type 21
154	image: 205314	Ughs.408312:175	tp53	nm_000546	tumor protein p53 (li-fraumeni	SEQ ID NO: 1735
					syndrome)
348	image: 35072	Ughs.76152:175	aqp1	nm_000385,	aquaporin 1 (channel-forming	SEQ ID NO: 1736
				nm_198098	integral protein, 28 kda)	SEQ ID NO: 1737
404	image: 41452	Ughs.28491:175	sat	nm_002970	spermidine/spermine n1-	SEQ ID NO: 1636
					acetyltransferase
412	image: 42214	Ughs.192182:175	syk	nm_003177	spleen tyrosine kinase	SEQ ID NO: 1738
416	image: 430090	Ughs.355307:175	tnfrsf7	nm_001242	tumor necrosis factor receptor	SEQ ID NO: 1739
					superfamily, member 7
431	image: 45831	Ughs.279920:175	ywhab	nm_003404,	tyrosine 3-	SEQ ID NO: 1740
				nm_139323	monooxygenase/tryptophan 5-	SEQ ID NO: 1741
					monooxygenase activation protein,
					beta polypeptide
451	image: 488316	Ughs.368256:175	ltbp1	nm_000627,	latent transforming growth factor	SEQ ID NO: 1742
				nm_206943	beta binding protein 1	SEQ ID NO: 1743
479	image: 510161	Ughs.1600:175	cct5	nm_012073	chaperonin containing tcp1, subunit 5	SEQ ID NO: 1744
					(epsilon)
486	image: 512000	Ughs.411826:175	ube2d3	nm_003340,	ubiquitin-conjugating enzyme e2d 3	SEQ ID NO: 1745
				nm_181886,	(ubc4/5 homolog, yeast)	SEQ ID NO: 1746
				nm_181887,		SEQ ID NO: 1747
				nm_181888,		SEQ ID NO: 1748
				nm_181889,		SEQ ID NO: 1749
				nm_181890,		SEQ ID NO: 1750
				nm_181891,		SEQ ID NO: 1751
				nm_181892,		SEQ ID NO: 1752
				nm_181893		SEQ ID NO: 1753
498	image: 530034	Ughs.544630:175			transcribed locus
535	image: 549173	Ughs.192023:175	eif3s2	nm_003757	eukaryotic translation initiation	SEQ ID NO: 1754
					factor 3, subunit 2 beta, 36 kda
622	image: 79598	Ughs.194657:175	cdh1	nm_004360	cadherin 1, type 1, e-cadherin	SEQ ID NO: 1755
					(epithelial)

In a further preferred embodiment, the sets for analyzing differential gene expression associated with MSI phenotype can, for example, consist of those mentioned in Table 6:

TABLE 6
			Gene	Reference
Set	Clone identifier	Cluster	Symbol	sequences	Title of cluster	SEQ ID Numbers
109	image: 159885	ughs.298469:175	Ace	nm_000789,	angiotensin i converting enzyme	SEQ ID NO: 1731
				nm_152830	(peptidyl-dipeptidase a) 1	SEQ ID NO: 1732
				nm_152831		SEQ ID NO: 1733
154	image: 205314	ughs.408312:175	tp53	Nm_000546	tumor protein p53 (li-fraumeni	SEQ ID NO: 1735
					syndrome)
412	image: 42214	ughs.192182:175	Syk	Nm_003177	spleen tyrosine kinase	SEQ ID NO: 1738
486	image: 512000	ughs.411826:175	ube2d3	nm_003340,	ubiquitin-conjugating enzyme e2d 3	SEQ ID NO: 1745
				nm_181886	(ubc4/5 homolog, yeast)	SEQ ID NO: 1746
				nm_181887		SEQ ID NO: 1747
				nm_181888		SEQ ID NO: 1748
				nm_181889		SEQ ID NO: 1749
				nm_181890		SEQ ID NO: 1750
				nm_181891		SEQ ID NO: 1751
				nm_181892		SEQ ID NO: 1752
				nm_181893		SEQ ID NO: 1753
535	image: 549173	ughs.192023:175	eif3s2	Nm_003757	eukaryotic translation initiation	SEQ ID NO: 1754
					factor 3, subunit 2 beta, 36 kda
622	image: 79598	ughs.194657:175	cdh1	Nm_004360	cadherin 1, type 1, e-cadherin	SEQ ID NO: 1755
					(epithelial)

In a further embodiment, the method of the present invention is directed to the analysis of differential gene expression associated with survival and death of patients in colon cancer. In this embodiment, said analysis comprises the detection of the overexpression or the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequences sets consisting of sets:

2; 3; 5; 7; 8; 10; 12; 14; 20; 22; 23; 26; 28; 32; 33; 35; 36; 41; 42; 44; 47; 50; 51; 60; 61; 63; 64; 70; 73; 74; 81; 92; 93; 95; 106; 115; 118; 120; 121; 123; 129; 130; 132; 133; 137; 145; 148; 149; 160; 161; 162; 163; 183; 187; 188; 195; 199; 200; 202; 206; 209; 211; 213; 214; 217; 219; 222; 228; 229; 230; 233; 234; 238; 245; 246; 247; 250; 257; 269; 271; 274; 275; 276; 282; 283; 284; 285; 289; 291; 292; 296; 302; 303; 304; 312; 314; 318; 323; 327; 333; 334; 335; 336; 337; 339; 340; 341; 342; 344; 345; 347; 350; 351; 356; 359; 361; 362; 363; 364; 367; 370; 373; 374; 378; 380; 381; 382; 383; 384; 387; 389; 402; 403; 408; 411; 414; 418; 420; 428; 430; 433; 435; 439; 444; 446; 447; 449; 456; 457; 458; 460; 461; 465; 473; 478; 482; 484; 489; 490; 491; 494; 497; 501; 502; 504; 510; 514; 516; 520; 523; 528; 529; 530; 536; 537; 538; 539; 540; 548; 551; 556; 561; 562; 570; 571; 580; 581; 582; 584; 586; 590; 591; 593; 594; 596; 603; 607; 609; 612; 615; 620; 624; 625; 628; 635; 639; and 640.

The analysis can comprise at least one of the following steps:

• • The detection of the overexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof selected from each of predefined polynucleotide sequence sets consisting of sets:

5; 14; 36; 44; 61; 64; 70; 81; 95; 115; 121; 132; 183; 209; 228; 275; 333; 334; 350; 367; 373; 435; 439; 523; 570; 603; and 625.

• • The detection of the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

2; 3; 7; 8; 10; 12; 20; 22; 23; 26; 28; 32; 33; 35; 41; 42; 47; 50; 51; 60; 63; 73; 74; 92; 93; 106; 118; 120; 123; 129; 130; 133; 137; 145; 148; 149; 160; 161; 162; 163; 187; 188; 195; 199; 200; 202; 206; 211; 213; 214; 217; 219; 222; 229; 230; 233; 234; 238; 245; 246; 247; 250; 257; 269; 271; 274; 276; 282; 283; 284; 285; 289; 291; 292; 296; 302; 303; 304; 312; 314; 318; 323; 327; 335; 336; 337; 339; 340; 341; 342; 344; 345; 347; 351; 356; 359; 361; 362; 363; 364; 370; 374; 378; 380; 381; 382; 383; 384; 387; 389; 402; 403; 408; 411; 414; 418; 420; 428; 430; 433; 444; 446; 447; 449; 456; 457; 458; 460; 461; 465; 473; 478; 482; 484; 489; 490; 491; 494; 497; 501; 502; 504; 510; 514; 516; 520; 528; 529; 530; 536; 537; 538; 539; 540; 548; 551; 556; 561; 562; 571; 580; 581; 582; 584; 586; 590; 591; 593; 594; 596; 607; 609; 612; 615; 620; 624; 628; 635; 639; and 640.

In a preferred embodiment the sets for analyzing differential gene expression associated with the survival and death of patients may for example consist of those mentioned in Table 7:

TABLE 7
			Gene	Reference
Set	Clone identifier	cluster	Symbol	sequences	Title of cluster	SEQ ID Numbers
10	image: 108370	ughs.366546:175	map2k2	nm_030662	mitogen-activated protein kinase	SEQ ID NO: 1756
					kinase 2
12	image: 108399
33	image: 121265	ughs.181315:175	ifnar1	nm_000629	interferon (alpha, beta and omega)	SEQ ID NO: 1683
					receptor 1
214	image: 257445	ughs.77917:175	uchl3	nm_006002	ubiquitin carboxyl-terminal esterase	SEQ ID NO: 1757
					13 (ubiquitin thiolesterase)
217	image: 258313	ughs.432170:175	cox7b	nm_001866	cytochrome c oxidase subunit viib	SEQ ID NO: 1685
271	image: 301119	ughs.80691:175	ckmt2	nm_001825	creatine kinase, mitochondrial 2
					(sarcomeric)
344	image: 346610	ughs.184510:175	sfn	nm_006142	stratifin	SEQ ID NO: 1758
383	image: 37630	ughs.300701:175	mgc8685	nm_178012	tubulin, beta polypeptide paralog	SEQ ID NO: 1759
387	image: 376755	ughs.24341:175	taz	nm_015472	transcriptional co-activator with pdz-	SEQ ID NO: 1760
					binding motif (taz)
414	image: 428103	ughs.1311:175	Cd1c	nm_001765	cd1c antigen, c polypeptide	SEQ ID NO: 1761
473	image: 509588	ughs.421646:175	taf12	nm_005644	taf12 rna polymerase ii, tata box	SEQ ID NO: 1706
					binding protein (tbp)-associated
					factor, 20 kda
484	image: 510977	ughs.173724:175	ckb	nm_001823	creatine kinase, brain	SEQ ID NO: 1707
516	image: 544885	ughs.469653:175	rp15	nm_000969	ribosomal protein 15	SEQ ID NO: 1708
536	image: 549178	ughs.448580:175;	sec611;	nm_007277;	sec6-like 1 (s. cerevisiae); tyrosine 3-	SEQ ID NO: 1762
		ughs.74405:175	ywhaq	nm_006826	monooxygenase/tryptophan 5-	SEQ ID NO: 1763
					monooxygenase activation protein,
					theta polypeptide
561	image: 611623	ughs.124979:175;	dj159a19.3;	nm_020462;	hypothetical protein dj159a19.3;	SEQ ID NO: 1764
		ughs.519765:175	kiaa1181		kiaa1181 protein

In a further embodiment the method of the present invention is directed to the analysis or differential gene expression associated with the location of primary colorectal carcinoma in colon cancer. In this embodiment, said analysis comprises the detection of the overexpression or the underexpression of a pool of polynucleotide sequences in colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected in from of predefined polynucleotide sequence sets consisting of sets:

6; 19; 43; 49; 83; 89; 94; 100; 151; 168; 172; 177; 224; 252; 258; 265; 309; 315; 316; 320; 322; 328; 355; 365; 391; 443; 453; 455; 466; 483; 496; 499; 506; 512; 513; 515; 517; 531; 532; 554; 563; 575; 579; 606; 618; and 637.

The analysis can comprise at least one of the following steps:

• • The detection of the overexpression of a pool of polynucleotide sequences in left-colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof selected from each of predefined polynucleotide sequence sets consisting of sets:

19; 43; 89; 94; 100; 168; 224; 309; 328; 355; 391; 466; 531; 532; 563; and 637.

• • The detection of the overexpression of a pool of polynucleotide sequences in right-colon tissues, said pool corresponding to all or part of the polynucleotide sequences, subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets consisting of sets:

6; 49; 83; 151; 172; 177; 252; 258; 265; 315; 316; 320; 322; 365; 443; 453; 455; 483; 496; 499; 506; 512; 513; 515; 517; 554; 575; 579; 606; and 618.

In a preferred embodiment, the sets for analyzing differential gene expression associated with the location of the primary colorectal carcinoma can, for example, consist of those mentioned in Table 8:

TABLE 8
			Gene	Reference
Set	Clone identifier	cluster	Symbol	sequences	Title of cluster	SEQ ID Numbers
43	image: 124345	ughs.77204:175	cenpf	nm_016343	centromere protein f, 350/400 ka	SEQ ID NO: 1765
					(mitosin)
100	image: 154335	ughs.321234:175	exosc10	nm_001001998,	exosome component 10	SEQ ID NO: 1766
				nm_002685		SEQ ID NO: 1767
151	image: 204653	ughs.174142:175	csf1r	nm_005211	colony stimulating factor 1 receptor,	SEQ ID NO: 1768
					formerly mcdonough feline sarcoma
					viral (v-fms) oncogene homolog
172	image: 22295	ughs.343220:175	crk	nm_005206,	v-crk sarcoma virus ct10 oncogene	SEQ ID NO: 1769
				nm_016823	homolog (avian)	SEQ ID NO: 1770
265	image: 291448	ughs.95972:175	silv	nm_006928	silver homolog (mouse)	SEQ ID NO: 1771
315	image: 325641	ughs.534030:175	psg5	nm_002781	pregnancy specific beta-1-	SEQ ID NO: 1772
					glycoprotein 5
443	image: 47986	ughs.149609:175	itga5	nm_002205	integrin, alpha 5 (fibronectin	SEQ ID NO: 1652
					receptor, alpha polypeptide)
499	image: 530037	ughs.244230:175			full-length cdna clone cs0di056yj24
					of placenta cot 25-normalized of
					homo sapiens (human)
532	image: 549065	ughs.169744:175	g22p1	nm_001469	thyroid autoantigen 70 kda (ku	SEQ ID NO: 1773
					antigen)
554	image: 594120	ughs.8364:175	pdk4	nm_002612	pyruvate dehydrogenase kinase,	SEQ ID NO: 1774
					isoenzyme 4

Tables 2 to 8 provide, for each set listed, certain features, some of which are redundant with Table 1 and some of which are additional. For instance, certain reference sequences (“NM_xxxxxx”) in the “Reference Sequences” column of Tables 2 to 8 are supplemental to the sequences mentioned in the “Ref.” column of Table 1. This “Reference Sequences” column provides one or more mRNA references for a specific corresponding gene. These mRNAs, that represent the various splice forms currently identified in the art, are encompassed by the nucleotide sequence sets listed in Tables 2 to 8. Each of these mRNAs can be considered as a marker in the meaning of the present invention. The use of the “NM_xxxxxx” references herein would be clearly understood by a person skilled in the art who is familiar with this type of referencing system. The sequences corresponding to each “NM_xxxxxx” reference (or corresponding splice forms) are available, e.g., in the OMIM and LocusLink databases (NCBI web site) and are incorporated herein by reference. An “NM_xxxxxx” reference is therefore a constant; i.e., it will always designate the same sequence over time and whatever the source (database, printed document, or the like).

Each set described herein comprises sequence(s) mentioned in Table 1 and, in addition, can comprise the “NM_XXXXXX” sequence and splice form(s) thereof mentioned in Tables 2 to 8 for each same set. For example, the sequences that comprise Set 1 are SEQ ID No. 1, 2 (of Table 1) and nm_—001747 sequence (of Table 2), including subsequences, or complements thereof, as described previously. In case of redundancy between the “Ref.” column of Table 1 and the “References Sequences” column of Tables 2 to 8 (i.e., if a “NM_XXXXXX” reference sequence corresponds to a SEQ ID sequence already mentioned in “Ref” column of Table 1), only one of these sequences may be considered.

The present invention further relates to a polynucleotide library useful for the molecular characterization of a colon cancer, comprising or corresponding to a pool of polynucleotide sequences which are either overexpressed or underexpressed in one or more of the above-cited tissues (e.g., colon tissue) said pool corresponding to all or part of the polynucleotide sequences (or markers) selected as defined above.

The detection of over or under expression of polynucleotide sequences according to the method of the invention can be carried out by fluorescence in-situ hybridization (FISH) or immuno histochemical (IHC), methods. Such detection can be performed on nucleic acids from a tissue sample, e.g., from one or more of the above-cited tissues, e.g., colorectal tissue sample, or from a tumor cell line.

The invention also relates particularly to a method performed on DNA or cDNA arrays; e.g., DNA or cDNA microarrays.

The detection of over or under expression of polynucleotide sequences according to the method of the invention can also be carried out at the protein level. Such detections are performed on proteins expressed from nucleic acid in one or more of the above-cited tissue samples.

Accordingly, a further method according to the present invention comprises:

a) obtaining a sample comprising proteins from a colorectal tissue sample from a subject; and

b) measuring in said sample obtained in step (a) the level of those proteins encoded by a polynucleotide library according to the invention.

The present invention is useful for detecting, diagnosing, staging, classifying, monitoring, predicting, and/or preventing colorectal cancer. It is particularly useful for predicting clinical outcome of colon cancer and/or predicting occurrence of metastatic relapse and/or determining the stage or aggressiveness of a colorectal disease in at least about 50%, e.g., at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% of the subjects. The invention is also useful for selecting a more appropriate dose and/or schedule of chemotherapeutics and/or biopharmaceuticals and/or radiation therapy to circumvent toxicities in a subject.

By “aggressiveness of a colorectal disease” is meant, e.g., cancer growth rate or potential to metastasize; a so-called “aggressive cancer” will grow or metastasize rapidly or significantly affect overall health status and quality of life.

By “predicting clinical outcome” is meant, e.g., the ability for a skilled artisan to classify subjects into at least two classes (good vs. poor prognosis) showing significantly different long-term Metastasis Free Survival (MFS).

In particular, the method of the invention is useful for classifying cell or tissue samples from subjects with histopathological features of colorectal disease, e.g., colon tumor or colon cancer, as samples from subjects having a “poor prognosis” (i.e., metastasis or disease occurred within 5 years since diagnosis) or a “good prognosis” (i.e., metastasis- or disease-free for at least 5 years of follow-up time since diagnosis).

The present invention further relates to a method of assigning a therapeutic regimen to subject with histopathological features of colorectal disease, for example colon cancer, comprising:

a) classifying said subject having a “poor prognosis” or a “good prognosis” on the basis of the method of analysing according to the present invention;

b) assigning said subject a therapeutic regimen, said therapeutic regimen (i) comprising no adjuvant chemotherapy if the subject is lymph node negative and is classified as having a good prognosis, or (ii) comprising chemotherapy if said subject has any other combination of lymph node status and expression profile.

For example, the assigning of a therapeutic regimen can comprise the use of an appropriate dose of irinotecan drug compound. For example, this dose is selected according to the presence or the absence of a polymorphism(s) in a uridine diphosphate glucuronosyltransferase I (UGT1A1) gene promoter of the subject. For example, a polymorphism may be the presence of an abnormal number of (TA) repeats in said UGT1A1 promoter.

More generally, the invention is also useful for selecting appropriate doses and/or schedules of chemotherapeutics and/or (bio)pharmaceuticals, and/or targeted agents, which can include irinotecan, 5-fluorouracil, fluorouracil, levamisole, mitomycin, lomustine, vincristine, oxaliplatin, methotrexate, and anti-thymidilate synthase. Further relevant anti-colorectal cancer agents are known in the art. These agents may administered alone or in combination.

The method for analyzing differential gene expression associated with histopathologic features of colorectal disease according to the present invention, e.g., the method for classifying cell or tissue samples, allows one to achieve high specificity and/or sensitivity levels of at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

By “specificity” is meant:Number of true negative samples×100/(Number of true negative samples+Number of false positive samples)

By “sensitivity” is meant:Number of true positive samples×100/(Number of true positive samples+Number of false negative samples)

With reference to the figures:

FIG. 1 shows global gene expression profiles in colorectal cancer and non-cancerous samples. 1A—Hierarchical clustering of 50 samples and ˜9,000 cDNA clones based on mRNA expression levels. Each row represents a clone and each column represents a sample. Expression level of each gene in a single sample is relative to its median abundance across all samples and depicted according to a color scale shown at the bottom. Red and green indicate expression levels above and below the median, respectively. The magnitude of deviation from the median is represented by the color saturation. Grey indicates missing data. Dendrogram of samples (above matrix) and genes (to the left of matrix) represent overall similarities in gene expression profiles. For samples, black branches represent normal tissues (n=23), red branches represent cancer tissues (n=22) and purple branches represent cancer cell lines (n=5). Colored bars to the right indicate the locations of 7 gene clusters of interest. These clusters, except the “proliferation cluster” (brown bar), are zoomed in B. 1B—Top panel: dendrogram of samples: tissue samples are designated with numbers followed by N when non-cancerous tissue and T when tumor tissue. Lower panel: expanded view of selected gene clusters named from top to bottom: “MHC class II”, “stromal”, “MHC class I”, “interferon-related”, “early response”, “smooth muscle” and “proliferation”. Genes are referenced by their HUGO abbreviation as used in “Locus Link”. 1C—Dendrogram of samples representing the results of the same hierarchical clustering applied only to the 22 cancer tissue samples. Two groups of samples (A and B) are defined. Sample names and branches highlighted in blue and in red represent patient samples without and with metastatic disease at diagnosis (labelled by *) or during follow-up, respectively. Status of each patient at last follow-up is marked by A (alive) or D (deceased)from CRC.

FIG. 2 shows hierarchical classification of tissue samples using genes which discriminate between normal and cancer samples. 2A—Hierarchical clustering of the 45 colon tissue samples using expression levels of the 245 cDNA clones were significantly different between normal and cancer samples. Dendrogram of these samples are magnified in B. 2B—Dendrogram of samples: black branches represent normal tissues (n=23) and red branches represent cancer tissues (n=22).

FIG. 3 shows hierarchical classification of CRC tissue samples using genes that discriminate metastatic from non-metastatic samples, correlated with survival. 3A—Hierarchical clustering of the 22 CRC tissue samples based on expression levels of the 244 cDNA clones was significantly different between metastatic and non-metastatic cancer samples. Dendrogram of samples is zoomed in B. 3B—Dendrogram of samples: blue represents samples without metastasis and red represents samples with metastasis at diagnosis (labelled by *) or during follow-up. A means alive at last follow-up and D means dead, from CRC. The analysis delineates 2 groups of tumors, group 1 and group 2. 3C—Kaplan-Meier plots of metastasis-free survival and overall survival of the 2 groups of samples defined by hierarchical clustering for all patients (left, n=22) and AJCC 1-3 patients (right, n=16).

FIG. 4 shows hierarchical classification of CRC tissue samples using discriminator genes selected by supervised analyses based on lymph node status, MSI phenotype and location of tumors. 4A—Hierarchical clustering of the 21 CRC tissue samples based on expression levels of the 46 cDNA clones significantly different between lymph node-positive (LN+, n=5, red branches and names) and lymph node-negative (LN−, n=16, blue branches and names) cancer samples. Each gene is identified by IMAGE cDNA clone number, HUGO abbreviation, and chromosomal location. EST means expressed sequence tag for clones without significant identity to a known gene or protein. 4B—Hierarchical clustering of the 22 CRC tissue samples based on expression levels of the 58 cDNA clones significantly different between MSI+ (MSI, n=8, blue branches and names) and non-MSI (n=14, red branches and names) cancer samples. 4C—Hierarchical clustering of the 22 CRC tissue samples based on expression levels of the 46 cDNA clones was significantly different between cancer samples from right colon (R, n=6, blue branches and names) and left colon (L, n=13, red branches and names).

FIG. 5 shows analysis of NM23 protein expression in colorectal tissue samples using tissue microarrays. Protein expression of NM23 was analysed using tissue microarrays containing 190 pairs of cancer samples and corresponding normal mucosa. 5A—Hematoxylin & Eosin staining of a paraffin block section (25x30) from a tissue microarray containing 216 tumors (3×55) and control samples. 5B—Five-μm sections of 0.6 mm core biopsies of cancer colorectal samples stained with anti-NM23 antibody are shown. Sections e and f are from CRC patients without metastasis (strong staining) and Sections g and h are from CRC patients with metastasis (low staining). 5C—Kaplan-Meier plots of overall survival in AJCC1-3 patients according to NM23 protein expression levels. Magnification is 50× in B-E.

EXAMPLE

The invention will now be illustrated with the following non-limiting examples.

1) Gene expression profiling of CRC and unsupervised classification

The mRNA expression profiles of 50 cancer and non-cancerous colon samples, including 45 clinical tissue samples and 5 cell lines, were determined using DNA microarrays containing ˜9,000 spotted PCR products from known genes and ESTs. Both unsupervised and supervised analyses were performed on all samples following normalization of expression levels.

Unsupervised hierarchical clustering of all samples based on the total gene expression profile was first applied. Results were displayed in a color-coded matrix (FIG. 1A) where samples were ordered on the horizontal axis and genes on the vertical axis on the basis of similarity of their expression profiles. The 50 samples were sorted into two large clusters that extensively differed with respect to normal or cancer type (FIG. 1B, top): 87% were non-cancerous in the left cluster and 87% were cancerous in the right cluster. As expected, the CRC cell lines represented a branch of the “cancer” cluster. Hierarchical clustering also allowed identification of clusters of gene expression corresponding to defined functions or cell types, some of which are indicated by colored bars on the right of FIG. 1A, and which are zoomed in FIG. 1B. Three clusters are overexpressed in tissue samples overall as compared to epithelial cell lines, reflecting the cell heterogeneity of tissues: an “immune cluster” with different subclusters including a MHC class I subcluster that correlated with an interferon-related subcluster, a MHC class II subcluster, which is a “stromal cluster” enriched with genes expressed in stromal cells (COL1A1, COL1A2, COL3A1, MMP2, TIMP1, SPARC, CSPG2, PECAM, INHBA), and a “smooth muscle cluster” (CNN1, CALD1, DES, MYH11, SMTN, TAGL) that was globally overexpressed in normal tissue as compared to cancer tissues. An “early response cluster” included immediate-early genes (JUNB, FOS, EGR1, NR4A1, DUSP1) involved in the human cellular response to environmental stress. Conversely, a very large cluster, defined as a “proliferation cluster”, was generally overexpressed in cell lines as compared to tissues, probably reflecting the proliferation rate difference between cells in culture and tumor tissues. This cluster included PCNA that codes for a proliferation marker used in clinical practice, as well as many genes involved in: glycolysis, such as GAPD, LDHA, ENO1; cell cycle and mitosis, such as CDK4, BUB3, CDKN3, GSPT2; metabolism, such as ALDH3A1, cytochrome C oxidase subunits, and GSTP1, and protein synthesis such as genes coding for ribosomal proteins.

The same clustering algorithm applied only to the 22 CRC clinical samples sorted two groups of tumors (A, 10 patients and B, 12 patients) that differed with respect to AJCC stage and clinical outcome (FIG. 1C). Group A included a high proportion of patients presenting with metastases at diagnosis (AJCC4 stage, 5 out of 10) as compared with group B (1 out of 12). Interestingly, 3 out of 5 “AJCC1-3” patients of group A experienced metastatic relapse after a median duration of 18 months (range, 4 to 88) from diagnosis and died from CRC, while none of the 11 “AJCC1-3” patients of group B relapsed or died after a median follow-up of 69 months (range, 10 to 98). This suggests that patients are at higher risk for metastasis in group A than in group B. To identify particular sets of genes that could better define subgroups of samples, supervised analyses were then conducted.

2) Differential gene expression between normal colon and colon tumors

To identify and rank genes with significant differential expression between cancer (22 samples) and non-cancerous colon tissues (23 samples), a discriminating score (DS) combined with iterative random permutation tests was applied. Two hundred forty-five cDNA clones, 130 of which were overexpressed and 115 were underexpressed in cancer samples, were identified. These clones corresponded to 237 unique sequences that represented 191 different known genes and 46 ESTs. The function of the known genes, as given in the OMIM and LocusLink databases (NCBI web site), are listed in Table. 1 above. Samples were then reclustered on the basis of these genes (FIG. 2), with a good resulting discrimination between normal and cancer samples: in the left branch 90% of samples were cancerous, while in the large right branch 92% were normal.

3) Differential gene expression within CRC tissue samples

A supervised approach was applied to the 22 cancer tissue samples by comparing tumor subgroups defined by relevant histoclinical parameters.

3.a) Genes associated with visceral metastases

The occurrence of metastasis is the leading cause of death in patients with CRC. Accurate predictors of metastasis are needed to determine therapeutic strategies and improve survival. Two hundred forty-four cDNA clones, corresponding to 235 unique sequences representing 194 characterized genes and 41 ESTs, were identified that discriminated between primary tumor samples collected from patients with and without metastasis at time of diagnosis or during follow-up. Among these clones, 219 were underexpressed and 25 were overexpressed in metastatic samples as compared to non-metastatic samples. Hierarchical clustering of samples based on expression of these selected genes (FIGS. 3A-B) successfully classified patients according to outcome, with only two non-metastatic samples misplaced in the group 2. Significantly, differences of survival between the two groups were statistically significant (FIG. 3C). The 5-year MFS (Metastatic Free Survival) and OS (Overall Survival) were 100% for group 1 (n=11) and 18% and 30%, respectively, for group 2 (n=11) (p=0.0001 and p=0.001). MFS and OS were 100% for group 1 (n=11) and 40% for the group 2 (n=5) when only patients without metastatic disease at time of diagnosis (AJCC1-3 stage) were considered (p=0.005 and p=0.006, respectively). Finally, MFS and OS were 100% for group 1 (n=10) and 50% for the group 2 (n=4) when only AJCC1-2 patients (no metastatic disease and node-negative tumor at time of diagnosis) were considered (p=0.019 and p=0.022, respectively).

3.b) Genes associated with lymph node metastases

Pathological lymph node involvement at diagnosis is a strong prognostic parameter in CRC. Its determination relies on surgical dissection, which currently requires biopsy of individual lymph nodes. Surgical lymph-node biopsy has major disadvantages, such as patient discomfort and the fact that metastases, particularly micrometastases, are often missed by surgical biopsy. Lymph node involvement is dependent on the heterogenous expression, and complex interaction(s) of these genes, to promote metastatic invasion and clinical outcome. Large-scale expression analyses provide a solution to identify these genes and the complexity of their interactions to drive tumorigenesis and metastatic invasion, as reported for breast or gastric cancers.

Forty-six cDNA clones (41 known genes and 5 ESTs) were identified as significantly differentially expressed between tumors with (n=5) and without (n=16) lymph node metastasis. Reclustering based on these 46 genes correctly separated node-positive from node-negative samples (FIG. 3A). The two samples (9075T and 7442T) that, among all node-negative cases, had expression patterns more closely related to node-positive samples, displayed metastatic disease at time of diagnosis (7442T) and 23 months after surgery (9075T), corroborating the predictions based on molecular signature.

3.c) Genes associated with MSI phenotype and with location of cancer

To obtain additional insights in colorectal oncogenesis, differential gene expression between MSI+(n=8) and non-MSI (n=14) tumors and between tumors from right colon (n=6) and left colon (n=13) were analyzed.

Fifty-eight cDNA clones (representing 51 known genes and 5 ESTs) with significant differential expression between MSI+ and non-MSI tumors were identified. The discriminator potential of these clones was confirmed by hierarchical classification of samples based on their expression levels, even if some MSI+ tumors displayed an intermediate expression profile (FIG. 4B). Similarly, classification of 19 samples (excluding transverse colon tumors), based on the expression of 46 cDNA genes (35 known genes and 11 ESTs) differentially expressed between right and left colon cancers, correctly sorted samples from the right or left colon (FIG. 4C). Such discrimination agreed with the existence of two distinct categories of CRC according to the location of tumor

3.d) Immunohistochemistry on tissue microarrays.

The protein expression levels of the most significant discriminatory genes identified by supervised analyses on TMA's containing 190 pairs of cancer samples and corresponding normal mucosa were measured. Use of TMA allowed the measurement of the expression levels simultaneously and in identical conditions. IHC results using an anti-NM23 antibody (which detects both NMEI and NME2 proteins)are shown in FIG. 5. Consistent with DNA microarray results, NM23 was significantly overexpressed in cancer samples as compared to non-cancerous samples (p=5.6×10⁻⁶, Fisher exact test), and was significantly down-regulated in tumors with metastasis (cut-off was the median value) compared to tumors without metastasis (p=0.04, Fisher exact test). The 5-year MFS was 68% for negative and 88% for positive samples when considering the 111 AJCC1-3 patients with available IHC data (p=0.02, log-rank test). Conversely, no such correlation, identified using DNA microarrays, was found for the protein expression levels of prohibitin and decorin.

4) Discussion

DNA microarray-based gene expression profiling is a promising approach to investigate the molecular complexity of cancer. To date, CRC studies have not directly addressed the issue of prognosis or MSI phenotype. Fifty cancer and non-cancerous colon tissue samples was profiled and expression profiles were correlated with histoclinical parameters of disease, including survival, using both unsupervised and supervised analyses.

4a) Unsupervised analysis

Global gene expression profile revealed extensive transcriptional heterogeneity between samples, notably cancer samples. It was to some extent already able to distinguish clinically relevant subgroups of samples: normal versus cancer tissues as previously reported, notably for CRC, and good versus poor prognosis tumors. Such global classification is usually imperfect because of the excessive noise generated by large gene sets that mask the identification of signicant discriminatory genes (such as clinical outcome) governed by a smaller set. Importantly, described global approach allows identification of discrete expression patterns to define clinical useful classification among patients with CRC: for example, several gene clusters that correspond to cell types (stroma, smooth muscle, MHC class I and II) or function (interferon-related, immediate-early response and proliferation) that have been reported in previous studies were identified; hence the validity of the present data consistent with putative biologic function.

4b) Supervised analyses

To identify smaller sets of discriminator genes that may improve classification of samples and facilitate translation in clinical practice, supervised statistical analyses were done, based on predefined groups of samples.

i) Comparison of normal vs cancer samples.

A total of 245 discriminator cDNA clones (3%) were significantly differentially expressed between normal and cancer samples. This ratio is in agreement with those reported in the literature. Comparison with lists of discriminator genes previously identified in CRC using DNA microarrays revealed many common genes, further underlying the validity of the present data. For example, CA4, CHGA, CNN1, MYH11, FCGBP, KCNMB1, SST were down-regulated, whereas CA3, CCT4, EIF3S6 or EEF1A1, IFITM1, CSE1L, NME1 or RAN were up-regulated in cancer samples. Beyond these common genes, many additional genes to improve the accuracy of previously described predictive signatures were identified.

Among the underexpressed genes in cancer samples were genes encoding cytokines (IL10RA, IL1RN, IL2RB), proteins involved in lipid metabolism (LPP, LIAS, LRP2, MGLL), signal transducers (PLCD1, PLCG2, mTOR/FRAP1), transcription factors such as RELA, and known or putative tumor suppressor genes (TSG). CTCF encodes a transcriptional repressor of MYC and is located in 16q22.1, a chromosomal region frequently deleted in breast and prostate tumors; IRF1, a transcriptional activator of genes induced by cytokines and growth factors, regulates apoptosis and cell proliferation and is frequently deficient in human cancers. The underexpression of GSN (gelsolin), combined with that of PRKCB1 (protein kinase C, beta 1), may lead to decreased activation of PKCs involved in phospholipid signalling pathways that inhibit cell proliferation and tumorigenicity.

The top-ranked gene overexpressed in cancer samples was GNB2L1 (also named RACK1) that encodes a beta polypeptide 2-like 1 of a guanine nucleotide binding protein (G protein) involved in signal transduction and activation of PKC. It also interacts with IGF1R, shown to play a pivotal role in colorectal oncogenesis; this interaction may regulate IGF1-mediated AKT activation and protection from cell death as well as IGF1-dependent integrin signalling and promote cell extravasion and contact with extracellular matrix (ECM). Other genes have already been reported as up-regulated in other types of cancer: they encode SNRPs and SOX transcription factors (SNRPC, SNRPE, SOX4, SOX9), components of ECM, and molecules involved in vascular and extracellular remodelling (COL5A1, P4HA1, MMP13, LAMR1). BZRP, that codes for the peripheral benzodiazepine receptor, cell cycle genes (CCNB2, CDK2), and SAT, involved in polyamine metabolism were also identified. Consistent with previous reports, we identified the overexpression in cancer samples of SERPINB5 and NME1, encoding two potential TSGs. Overexpression of NME1 combined with underexpression of CTCF interacts to induce overexpression of the MYC oncogene, an important modulator of WNT/APC signalling shown to play an important role in the development of CRC. Other up-regulated genes, and potential therapeutic targets, include kinases (PTK2, STK6, NTRK2), the cell-surface protein CD9, and three genes encoding integrins ITGA2, ITGAL and ITGB3. The integrin pathway was further affected with variations in the expression of genes encoding PTK2, TGFB1I1/HIC5 (a PTK2 interactor), and integrin-linked kinase ILK. Agrawal et al. previously identified osteopontin, an integrin-binding protein as a marker of CRC progression. SPP1 that codes for osteopontin, as well as CXCL1 which codes for GRO1 oncogene or CDK4, were not in the present stringent list of discriminator genes, although overexpressed in cancer samples with a fold-change greater or equal to 2.

Discriminator genes were associated with many cell structures, processes and functions, including general metabolism (the most abundant category), cell cycle, proliferation, apoptosis, adhesion, cytoskeletal remodelling, signal transduction, transcription, translation, RNA and protein processing, immune system and others. Up- and down-regulated genes were rather equally distributed with respect to these functions, except for those coding for kinases and for proteins involved in extracellular matrix remodelling, metabolism, RNA and protein processing (translation, ribosomal proteins and chaperonins), which were overexpressed in cancer samples as compared to normal samples. This phenomenon, already reported, is likely to be related to increased metabolism and cell proliferation in cancer cells.

Analysis of chromosomal location point to two interesting regions. Six genes up-regulated in cancer (STK6, UBE2C, PFDN4, RPS21, CSE1L, SLPI) were located in 20q13, a chromosomal region often amplified in cancer; their overexpression might be a consequence of gene amplification. This has already been observed by others, although not all genes of the region are affected transcriptionally. Conversely, six genes (TJP3, INSR, ELAVL1, MAP2K7, CNN1, NR2F6) down-regulated in cancer samples were located in 19p13.1-p13.3, already known to harbour several potential TSG such as APC2, STK11 or MCC2.

ii) Expression profiles and clinical outcome

All subjects, some of them presenting with metastasis at diagnosis, had received standard treatment. Significantly, the described method for global hierarchical clustering from subjects with non-metastatic tumors that clustered with metastatic cases eventually developed metastasis and died during follow-up. Supervised analysis further improved the prognostic classification by identifying 194 known genes and 41 ESTs that well discriminated between samples without or with metastasis at diagnosis or during follow-up. This is the first report that suggests a potential prognostic role of gene expression profiling in CRC. The significance of the prognostic classification made by AJCC stage and by expression levels of the present discriminator gene sets were compared. Classification based on AJCC stage (AJCC1-2 tumors, n=14, vs AJCC3-4 tumors, n=8) was significant (p=0.001; Kaplan-Meier survival analysis, log-rank test), but less than that made by expression profiles (Fisher's exact test, p=0.05 vs p=0.003). Significantly, the prognostic impact of our gene set was also confirmed when applied to patients without metastasis at diagnosis as well as to patients without metastasis and lymph node invasion.

In addition, the functional identities of the discriminator genes provided insight into the underlying molecular mechanism that drive the metastatic process, and contributed to the identification of potential novel therapeutic targets. For example, known genes that were down-regulated in metastatic tumors were DSC2, encoding desmocollin 2, a desmosomal and hemi-desmosomal adhesion molecule of the cadherin family, HPN, coding for hepsin, a transmembrane serine protease the favorable prognostic role of which has been recently highlighted in prostate cancer by studies using DNA and/or tissue microarrays. Decorin is a small leucine-rich proteoglycan abundant in ECM that negatively controls growth of colon cancer cells and angiogenesis. Low levels of mRNA have been associated with a worse prognosis in breast carcinomas. NME1 and NME2 were underexpressed in patients that developed metastasis, consistent with previous reports that these genes interacted to suppress metastasis. Prohibitin is a mitochondrial protein thought to be a negative regulator of cell proliferation and may be a TSG. Transcription of genes encoding mitochondrial proteins has been shown to be decreased during progression of CRC. This was confirmed in the present study, since all discriminator genes involved in mitochondrial metabolism were down-regulated in metastatic tumors (ATP5C1, BCKDK, CABC1, CKMT2, COX5B, COX6B, COX7A2, COX7A2L, COX7C, HSPA9B, LRIG1, MDH1, NDUFA1, NDUFA4, NDUFA6, NDUFA9, NDUFV1, SCO1, UQCR). Surprisingly, although increased protein synthesis is classically associated with oncogenic transformation, we found many genes coding for ribosomal proteins (RPL5, RPL6, RPL15, RPL29, RPL31, RPL39) were found that were down-regulated in metastatic tumors. The SMAD1/AMDH1 gene codes for a transmitter of TGFalpha signalling, which exerts a number of regulatory effects on colon cells and is involved in the metastatic process. The most significantly overexpressed genes in metastatic tumors were PCSK7, which codes for the proprotein convertase subtilisin/kexin type 7. Proprotein convertases (PCs) process latent precursor proteins into their biologically active products, including protein tyrosine phosphatases, growth factors and their receptors, and enzymes like matrix metalloproteases (MMPs), that may confer on them a functional role in the tumor cell invasion and tumor progression. Other up-regulated genes encoded various signalling proteins including PRAME, an interactor of the cytoskeleton-regulator paxillin, IQGAP1, a negative regulator of the E-cadherin/catenin complex-based cell-cell adhesion, LTPB4, a structural component of connective tissue microfibrils and local regulator of TGFβ tissue deposition and signalling, IGF1R, a transmembrane tyrosine kinase receptor, and DSG1, another desmosomal cadherin-like protein. The incorrect balance between the various desmosomal cadherins has been shown to facilitate separation of epithelial from the ECM and metastasis. IGF1R has been recently shown as involved in metastases of CRC by preventing apoptosis, enhancing cell proliferation, and inducing angiogenesis. Several genes located on the long arm of chromosome 15 were down-regulated in metastatic samples.

iii) Expression profiles and lymph node metastasis

Although nodal metastasis is currently the standard clinical method to predict patient prognosis, there is clear consensus that an improved diagnostic is required to accurately predict survival for patients with CRC. However, approximately one-third of node-negative CRC recur, possibly due to understaging and inadequate pathological examination of lymph nodes. Statistical models suggest that the mean number of nodes currently identified in patients is much too low to correctly classify nodal status. Expression profiles defined in primary tumors could help predict the presence of lymph node metastasis, as recently reported. Forty-six genes and ESTs were identified as discriminators between node-positive and node-negative tumors. Since lymph node status and metastatic relapse are correlated events, this invention includes the identification of novel genes that discriminate between tumors with or without metastasis.

For example, OAS1 and NTRK2 were overexpressed in node-positive tumors. NTRK2 encodes a neurotrophic tyrosine kinase, and aberrant mutation of NTRK2 has recently been shown to play a role in the metastastic process. OAS1 encodes the 2′,5′-oligoadenylate synthetase 1; the 2-5A system has been implicated in the control of cell growth, differentiation, and apoptosis. High levels of activity have been reported in individuals with disseminated cancer, and a recent study found overexpression of OAS1 mRNA in node-positive breast cancers. Conversely, MGP, PRSS8 and NME2 were down-regulated in node-positive tumors. MGP encodes the matrix G1a protein, the loss of expression of which has been associated with lymph node metastasis in urogenital tumors. The prostasin serine protease, encoded by PRSS8, is a potential invasion suppressor, and down-regulation of PRSS8 expression may contribute to invasiveness and metastatic potential. The present list of 46 discriminator clones also included additional genes, reflecting the non-perfect correlation between lymph node metastasis and visceral metastasis and the involvement of different underlying biological processes.

Among genes underexpressed in node-positive tumors were BUB3, TPP2 and ITIH1. BUB3 codes for a mitotic-spindle checkpoint protein that interacts with the APC protein to regulate chromosome segregation during cell division. Defects in mitotic checkpoints, including mutations of BUB1, have been associated with CRC and BUB genes (BUB1 and BUB1B) are underexpressed in highly metastatic colon cell lines. TPP2, encodes tripeptidyl peptidase II, a high molecular mass serine exopeptidase that may play a functional role by degrading peptides involved in invasive and metastatic potential as recently reported for another peptidyl peptidase DPP4. ITIH 1, encodes a heavy chain of proteins of the ITI family, that inhibits the metastatic spreading of H460M large cell lung carcinoma lines by increasing cell attachment.

iv) Expression profiles and MSI phenotype

Without wishing to be bound by any theory, it is believed that there are at least two distinct pathways of oncogenesis in sporadic CRC. Fifteen per cent of tumors present the MSI phenotype, which is related to the inactivation of MMR genes, principally MSH2 and MLH1. The genetically unstable tumor cells accumulate somatic clonal mutations in their genome, which may disturb mRNA expression or degradation of specific transcripts. Conversely, 85% of sporadic tumors are associated with a non-MSI (or MSS) phenotype; they are characterized by chromosome instability and loss of genomic material that may count for the loss of expression of specific alleles. MSI+ tumors are frequently diploid, located in the proximal colon, and may be associated with better prognosis and response to chemotherapy. Reliable distinction between MSI+ and non-MSI phenotypes, currently based on molecular approaches, remains problematic and difficult to assess/confirm in the clinical setting; largely due to the number and heterogeniety of genes involved, absence of easily identifiable mutationional hot-spots, and epigenetic inactivation. Other methods are being tested such as IHC assessment of MSH2 and MLH1

Although the underlying molecular mechanisms of MSI+ and non-MSI colorectal oncogenesis remain unclear, it appears that these two phenotypes represent different molecular entities that could translate into distinct gene expression profiles useful in clinical practice as new diagnostic markers and/or tests. The present supervised analysis of MSI+ and non-MSI CRC clinical samples showed 58 differentially expressed clones. It is of note that arrayed MMR genes (MSH2, MSH3, MLH1, MLH3, PMS1 and PMS2) were not among these discriminator genes. As reported for cell lines, several of these deregulated genes are involved in cell cycle control, mitosis, transcription and/or chromatin structure (RAN, PTPN21, TP53, MORF4L1, ZFP36L2, PSEN1, IGF2, ASNS, RPS4X, CCNF, ZNF354A). The top down-regulated gene in MSI+ tumors was EIF3S2, that encodes the eukaryotic translation initiation factor 3, and subunit 2β, also known as TRIP1 (TGFalpha receptor-interacting protein 1). TRIP1 specifically associates with TGFBRII, a serine/threonine kinase receptor frequently inactivated by mutation and down-regulated in MSI+ tumors.

v) Validation studies

Many different cell processes are aberantly modulated during colorectal oncogenesis. Genes involved in adhesion processes are affected in metastasis. Genes known to be affected in oncogenesis, such as MMR genes, do not discriminate tumor subgroups. DNA microarray data could prove rapidly useful in clinical practice and design of new therapeutic options. The described DNA micro-array approach may be ideally suited to elucidate the complex and heterogeneous processes that drive CRC progression in individual patients, significantly improve clinical treatment of CRC, and optimize the use of novel therapeutic options. Discriminator genes represent potential new diagnostic and prognostic markers and/or therapeutic targets, and deserve further investigation in larger series of subjects. Novel markers of potentially differentially expressed molecules were identified using IHC on TMA containing 190 pairs of cancer samples and corresponding normal mucosa. TMA confirmed the correlations between NM23 expression level and two clinical parameters: non-cancerous or cancer status and survival of patients. Expression was higher in cancer samples, and low expression was significantly associated with a shorter MFS. Such correlation has been described in a variety of malignant tumors, including breast, ovarian, lung or gastric cancers as well as melanoma. However, this correlation remains controversial in CRC, with positive and negative reports. The present invention allowed measurement of the expression levels simultaneously and under highly standardized conditions for all the 190 CRC samples, representing one of the largest series of CRC samples tested for NM23 IHC. 0 As previously described, correlation between protein and mRNA levels would not be expected in all cases. This was the case for Decorin and Prohibitin.

vi) Conclusion.

The data presented in this nonlimiting Examples section shows that mRNA expression profiling of CRC using DNA microarrays provides for identification of clinically relevant tumor subgroups, defined upon combined expression of genes. The genes delineated in this invention can contribute to the understanding of CRC development and progression, and may lead to improved and new diagnostic and/or prognostic markers, identify new molecular targets for novel anticancer drugs, and may also lead to significant improvements in CRC management.

V—Materials and Methods used in the above Examples

1) Colorectal cancer patients and samples

A total of 50 samples including 45 tissue samples and 5 cell lines were profiled using DNA microarrays. The 45 colon tissue samples were obtained from 26 unselected patients with sporadic colorectal adenocarcinoma who underwent surgery at the Institut Paoli-Calmettes (Marseille, France) between 1990 and 1998. Samples were macrodissected by pathologists, and frozen within 30 min of removal in liquid nitrogen for molecular analyses. All tumor samples contained more than 50% tumor cells. The 45 samples included 22 cancer samples and 23 normal samples divided into 19 tumor-normal pairs (based on availability of a sample of the corresponding normal colonic mucosa), 3 tumors and 4 normal specimens provided from different patients. All tumor sections and medical records were de novo reviewed prior to analysis. MSI phenotype of 22 cancer samples was determined by PCR amplification using BAT-25 and BAT-26 oligonucleotide primers, and by IHC using anti-MSH2 and MLH1 antibodies. BAT-25 and BAT-26 are mononucleotide repeat microsatellites: a polyA²⁶ sequence located in the fifth intron of MSH2 for BAT-26, and located in an intron of the KIT gene for BAT-25. Tumors with alterations in both BAT markers were classified as MSI+. No attempt was made to further classify tumors into MSI-high and MSI-low phenotype. Main characteristics of patients and tumors are listed in Table 9. After colonic surgery, subjects were treated (delivery of chemotherapy or not) according to standard guidelines. After completion of therapy, subjects were evaluated at 3-month intervals for the first 2 years and at 6-month intervals thereafter. Search for metastatic relapse included clinical examination and blood tests completed by yearly chest X-ray and liver ultrasound and/or CT scan.

Five samples were represented by 2 different sporadic colon cancer cell lines with chromosomal instability phenotype, Caco2 and HT29. Three samples represented Caco2 in a differentiated state (named Caco2A, 2B and 2C)—i.e. at confluence (C), at C+10 days, at C+21 days—and one sample represented undifferentiated Caco2 (named Caco2D). Cell lines were obtained from the American Type Culture Collection and grown as recommended.

TABLE 9
Characteristics of cancer samples profiled using DNA microarrays
								MSI		Outcome
Patient	Sex	Age	Location	Grade	pT UICC	pN UICC	AJCC Stage	status	Treatment	(months)
7650	M	74	descending colon	G	pT3	pN1	4 (liver)	MSI	pS + pCT	AWC 4
8582	F	80	ascending colon	P	pT3	pN3	4 (liver)	MSI	pS	D 1
7442	M	64	transverse colon	G	pT3	pN1	4 (liver)	MSS	pS + pCT	D 32
8208	M	40	transverse colon	M	pT3	pN2	4 (liver)	MSS	cS + adj CT	D 41
7835	F	72	transverse colon	G	pT3	pN3	4 (liver)	MSS	pS + pCT	D 17
8656	F	57	descending colon	G	pT3	pN2	4 (liver)	MSS	cS + adj CT	AWC 66
8031	F	46	descending colon	G	pT3	pN2	3	MSS	cS + adj CT	MR 4 - D 7
6927	M	71	descending colon	G	pT3	NA	NA	MSS	cS + adj CT	NED 10
9118	F	75	ascending colon	G	pT3	pN1	2	MSI	cS + adj CT	NED 56
8904	M	80	descending colon	G	pT3	pN1	2	MSI	cS	NED 18
6974	M	68	ascending colon	P	pT3	pN1	2	MSI	cS + adj CT	NED 97
8646	M	74	descending colon	G	pT3	pN1	2	MSS	cS	NED 63
8458	M	56	descending colon	G	pT3	pN1	2	MSS	cS + adj CT	NED 69
6992	F	65	ascending colon	G	pT3	pN1	2	MSS	cS + adj CT	NED 98
7094	F	87	descending colon	G	pT3	pN1	2	MSS	cS	NED 64
8252	F	54	rectum	G	pT4	pN1	2	MSS	cS + adj CT	NED 74
9075	F	45	ascending colon	G	pT2	pN1	1	MSI	cS	MR23 - D38
7505	M	71	ascending colon	G	pT1	pN1	1	MSI	cS	NED 88
7043	M	70	descending colon	G	pT2	pN1	1	MSS	cS	NED 97
6952	M	58	descending colon	G	pT2	pN1	1	MSS	cS	NED 65
7597	F	72	rectum	G	pT2	pN1	1	MSS	cS	NED 87
7815	M	63	rectum	G	pT2	pN1	1	MSI	cS	MR 10 - D 40

For the IHC study on Tissue Micro Array (TMA), a consecutive series of 191 sporadic CRC patients (including the 26 cases studied by DNA microarrays) treated between 1990 and 1998 at the Institut Paoli-Calmettes was selected. The study included 98 men and 92 women. The median age of patients at diagnosis was 64 years, (range, 29 to 97 years). In 58% of the cases, tumors were located in the distal part of the large bowel or sigmoid, 29% in the proximal part, and 13% in the rectum.

TABLE 10
Characteristics of cancer samples profiled using tissue microarrays.
Characteristics                  All patients (n = 191)
Sex (M/F)                        99/92
Median age, years (range)        64 (29-97)
Location of tumor
ascending colon                  47
transverse colon                 9
descending colon                 110
rectum                           21
na                               4
Grade
good                             127
poor                             50
na                               14
pT UICC
1                                16
2                                21
3                                127
4                                27
pN UICC
1                                88
2                                48
3                                54
Na                               1
Vascular invasion
no                               115
yes                              68
na                               8
AJCC stage*
1                                29
2                                51
3                                43
4                                68
Surgery                          191
curative/palliative              131/59
na                               1
Chemotherapy                     109
adjuvant/palliative              60/49
no chemotherapy                  80
na                               2
Median follow-up, months (range) 74 (2, 133)
Metastatic evolution             95
metastatic relapse*              27
progression**                    68
Death from CRC                   90
Legend:
M, male;
F, female;
na, not available;
pT, pathological staging of primary tumor;
UICC, International Union Against Cancer;
pN, pathological staging of regional lymph nodes;
AJCC, American Joint Committee on Cancer;
*AJCC1-3 patients;
**AJCC4 patients;
CRC, colorectal cancer.

2) RNA extraction

Total RNA was extracted from frozen tumor samples by using standard guanadinium isothiocynanate and cesium chloride gradient techniques. RNA integrity was controlled by denaturing formaldehyde agarose gel electrophoresis and 28-S Northern blots before labelling.

3) DNA microarray preparation

Gene expression analyses were performed with home-made Nylon microarrays containing 8,074 spotted cDNA clones, representing 7,874 IMAGE human cDNA clones and 200 control clones. According to the 155 Unigene release, the IMAGE clones were divided into 6,664 genes and 1,210 ESTs. All clones were PCR-amplified in 96-well microtiter plates (200 μl). Amplification products were desiccated and resuspended in 50 μl of distilled water. They were then spotted as previously described onto Hybond-N+2×7 cm² membranes (Amersham) adhered to glass slides, using a 64-pin print head on a MicroGridII microarrayer (Apogent Discoveries, Cambridge, England). All membranes used in this study belonged to the same batch.

4) DNA microarray hybridizations

Microarrays were hybridized with ³³P-labeled probes: first with an oligonucleotide sequence common to all spotted PCR products (called “vector hybridization” to precisely determine the amount of target DNA accessible to hybridisation in each spot) and then, after stripping, with complex probes made from 2 μg of retrotranscribed total RNA. Probe preparations, hybridizations and washes were done as previously described and available from the website maintained by TAGC ERM206 (INSERM) under the heading “Materials and Methods, ” the entire disclosure of which is herein incorporated by reference. After the washing steps, arrays were exposed to phosphor-imaging plates that were then scanned with a FUJI BAS 5000 machine (25 μm resolution). Hybridization signals were quantified using ArrayGauge software (Fuji Ltd, Tokyo, Japan).

5) Data analysis

Signal intensities were normalized for the amount of spotted DNA and the variability of experimental conditions (FB HMG99). Complex probe intensity of each spot (C) was first corrected (C/V) for the amount of target DNA accessible to hybridization as measured using vector hybridisation (V). When V intensity of a spot was too weak on a microarray, the corresponding cDNA clone was not considered for this experiment. Then, to minimize experimental differences between different complex probe hybridizations, C/V values from each hybridization were divided by the corresponding median value of C/V.

Unsupervised hierarchical clustering analysis then allowed the investigation of relationships between samples and between genes. This analysis was applied to data log-transformed and median-centred on genes using the Cluster and TreeView program (average linkage clustering using Pearson correlation as similarity metric). Supervised analysis was also used to identify and rank genes that distinguished between two subgroups of samples defined by an interesting histoclinical parameter. A discriminating score (DS) was calculated for each gene as DS=(M1−M2)/(S1+S2), where M1 and S1 respectively represent mean and standard deviation of expression levels of the gene in subgroup 1, and M2 and S2 in subgroup 2. Confidence levels were estimated by bootstrap resampling.

Statistical analyses were done using the SPSS software (version 10.0.5). Metastasis-free survival (MFS) and overall survival (OS) were measured from diagnosis until, respectively, the date of the first distant metastasis and the date of death from CRC. Survivals were estimated with the Kaplan-Meier method and compared between groups with the Log-Rank test. Data concerning patients without metastatic relapse or death at last follow-up were censored, as well as deaths from other causes. A p-value <0.05 was considered significant.

6) Tissue microarrays (TMA) construction

The technique of TMA allowed the analysis of tumors and their respective normal mucosa simultaneously and under identical experimental conditions for the 190 subjects. TMA were prepared as described above, with slight modifications. For each sample, three representative sample areas were carefully selected from a hematoxylin-eosin stained section of a donor block. Core cylinders with a diameter of 0.6 mm each were punched from each of these areas and deposited into three separate recipient paraffin blocks, using a specific arraying device (Beecher Instruments, Silver Spring, Md.). In addition to pairs of tumor and normal mucosa, the recipient block also received control tissue (small intestine, adenomas) and cell lines pellets. Five-μm sections of the resulting TMA block were made and used for IHC analysis after transfer onto glass slides. Two colon tumor cell lines (CaCo-2, HT29) and one gastric tumor cell line (HGT1) were used as controls.

7) Immunohistochemical analysis

Anti-NM23 rabbit polyclonal antibody was purchased from Dako (Dako, Trappes, France) and used at 1:100 dilution. IHC was carried out on five-μm sections of tissue fixed in alcohol formalin for 24 h and included in paraffin. Sections were deparaffinized in histolemon (Carlo Erba Reagenti, Rodano, Italy), and were rehydrated in graded alcohol. Antigen enhancement was done by incubating the sections in target retrieval solution (Dako) as recommended by the manufacturer. The reactions were carried out using an automatic stainer (Dako Autostainer). Staining was done at room temperature as follows: after washes in phosphate buffer, followed by quenching of endogenous peroxidase activity by treatment with 3% H₂O₂, slides were first incubated with blocking serum (Dako) for 30 min and then with the affinity-purified antibody for one hour. After washes, slides were incubated with biotinylated antibody against rabbit IgG for 20 min., followed by streptadivin-conjugated peroxydase (Dako LSAB^R2 kit). Diaminobenzidine or 3-amino-9-ethylcarbazole was used as the chromogen. Slides were counter-stained with hematoxylin, and coverslipped using Aquatex (Merck, Darmstadt, Germany) mounting solution. The slides were evaluated under a light microscope by two pathologists. The results were expressed in terms of percentage (P) and intensity (I) of positive cells as previously described: results were scored by the quick score (Q) (Q=P×I). For the TMA, the mean of the score of two core biopsies minimum was done for each case. Correlations between status of sample (non-cancerous or cancer, and cancer with or without metastasis) or Kaplan-Meier MFS curves and IHC data were investigated by using Fisher exact test and Log-Rank test. Statistical tests were two-sided at the 5% level of significance.

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Claims

1. A method for analyzing differential gene expression associated with histopathologic features of colorectal disease, comprising the detection of the overexpression or underexpression of a pool of polynucleotide sequences from colon tissues, said pool comprising all or part of the polynucleotide sequences, or subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets 1 through 644.

2. The method for analyzing differential gene expression associated with colon tumors according to claim 1, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 1; 4; 9; 10; 11; 13; 15; 16; 17; 18; 21; 27; 28; 30; 31; 34; 37; 39; 41; 43; 45; 46; 52; 53; 58; 59; 60; 65; 68; 69; 70; 75; 76; 78; 79; 80; 84; 85; 87; 88; 90; 95; 96; 98; 99; 101; 105; 108; 110; 111; 113; 114; 116; 119; 120; 122; 124; 125; 126; 127; 130; 131; 138; 139; 140; 141; 143; 150; 152; 153; 155; 159; 164; 171; 175; 176; 178; 181; 182; 184; 185; 189; 192; 196; 197; 198; 203; 205; 207; 208; 210; 213; 214; 215; 216; 218; 221; 223; 225; 227; 231; 235; 241; 243; 251; 256; 259; 261; 262; 263; 264; 266; 267; 268; 270; 279; 281; 286; 287; 288; 291; 298; 299; 301; 307; 310; 312; 313; 317; 319; 329; 331; 332; 337; 338; 339; 340; 341; 342; 344; 346; 352; 354; 357; 360; 361; 366; 368; 369; 377; 379; 381; 384; 385; 386; 390; 392; 394; 395; 397; 398; 400; 401; 405; 406; 409; 410; 413; 423; 427; 434; 436; 437; 438; 440; 442; 443; 444; 445; 448; 454; 459; 463; 464; 467; 469; 470; 488; 492; 495; 500; 503; 507; 508; 516; 518; 520; 522; 524; 538; 543; 547; 549; 552; 555; 557; 561; 567; 568; 569; 573; 574; 583; 586; 588; 592; 596; 597; 598; 599; 600; 601; 604; 609; 610; 611; 614; 616; 617; 621; 626; 627; 629; 630; 631; 632; 634; 635; 636; 638; 641; 642; and 644.

3. The method of claim 1, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 1; 9; 10; 16; 18; 27; 28; 30; 39; 41; 43; 45; 53; 58; 60; 65; 69; 75; 76; 113; 116; 120; 122; 126; 127; 130; 131; 138; 139; 140; 141; 143; 150; 152; 153; 159; 181; 182; 184; 189; 192; 197; 198; 210; 213; 214; 216; 218; 225; 227; 243; 259; 261; 264; 266; 267; 268; 281; 286; 287; 288; 291; 299; 307; 312; 313; 317; 319; 332; 337; 338; 339; 340; 341; 342; 344; 354; 357; 360; 361; 368; 381; 384; 385; 392; 394; 397; 398; 405; 423; 427; 442; 444; 464; 467; 469; 488; 495; 500; 507; 508; 516; 520; 522; 524; 538; 543; 547; 549; 552; 561; 567; 568; 569; 573; 586; 588; 592; 596; 600; 609; 614; 627; 629; 630; 635; 636; 641; 642; and 644.

4. The method of claim 1, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 4; 11; 13; 15; 17; 21; 31; 34; 37; 46; 52; 59; 68; 70; 78; 79; 80; 84; 85; 87; 88; 90; 95; 96; 98; 99; 101; 105; 108; 110; 111; 114; 119; 124; 125; 155; 164; 171; 175; 176; 178; 185; 196; 203; 205; 207; 208; 215; 221; 223; 231; 235; 241; 251; 256; 262; 263; 270; 279; 298; 301; 310; 329; 331; 346; 352; 366; 369; 377; 379; 386; 390; 395; 400; 401; 406; 409; 410; 413; 434; 436; 437; 438; 440; 443; 445; 448; 454; 459; 463; 470; 492; 503; 518; 555; 557; 574; 583; 597; 598; 599; 601; 604; 610; 611; 616; 617; 621; 626; 631; 632; 634; and 638.

5. The method of claim 1, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 2; 3; 10; 22; 24; 25; 30; 32; 33; 35; 36; 39; 40; 41; 42; 47; 50; 54; 57; 67; 72; 86; 97; 102; 103; 104; 107; 117; 118; 120; 128; 130; 132; 133; 134; 137; 144; 145; 146; 147; 149; 153; 156; 158; 162; 163; 165; 169; 170; 173; 174; 179; 180; 188; 191; 193; 194; 195; 199; 200; 201; 202; 204; 206; 209; 210; 211; 212; 213; 214; 216; 217; 219; 222; 234; 238; 246; 248; 249; 250; 255; 271; 272; 273; 276; 277; 278; 282; 283; 284; 291; 292; 293; 294; 295; 296; 303; 304; 305; 306; 308; 312; 314; 318; 323; 324; 325; 326; 330; 336; 337; 338; 339; 340; 341; 342; 343; 344; 347; 349; 350; 351; 353; 356; 359; 360; 361; 362; 363; 364; 371; 372; 374; 378; 380; 381; 382; 383; 384; 387; 388; 393; 396; 397; 399; 402; 403; 408; 414; 415; 417; 418; 419; 420; 421; 422; 426; 428; 430; 432; 433; 441; 446; 449; 457; 458; 460; 465; 471; 472; 473; 475; 476; 478; 480; 481; 482; 484; 485; 486; 490; 493; 494; 497; 501; 502; 504; 505; 509; 510; 514; 516; 520; 525; 526; 527; 528; 529; 530; 537; 538; 539; 541; 545; 546; 550; 558; 559; 560; 561; 562; 564; 565; 566; 571; 576; 577; 578; 580; 581; 584; 585; 586; 590; 591; 593; 594; 595; 596; 602; 607; 609; 612; 613; 615; 623; 624; 625; 633; 635; 639; 640; 643; and 644, and wherein differential gene expression associated with visceral metastases in colon cancer is detected.

6. The method of claim 5, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 36; 86; 104; 107; 117; 132; 144; 153; 156; 174; 191; 209; 248; 349; 350; 396; 417; 419; 432; 558; 566; 613; 623; 625; 633; and 643.

7. The method of claim 5, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 2; 3; 10; 22; 24; 25; 30; 32; 33; 35; 39; 40; 41; 42; 47; 50; 54; 57; 67; 72; 97; 102; 103; 118; 120; 128; 130; 133; 134; 137; 145; 146; 147; 149; 158; 162; 163; 165; 169; 170; 173; 179; 180; 188; 193; 194; 195; 199; 200; 201; 202; 204; 206; 210; 211; 212; 213; 214; 216; 217; 219; 222; 234; 238; 246; 249; 250; 255; 271; 272; 273; 276; 277; 278; 282; 283; 284; 291; 292; 293; 294; 295; 296; 303; 304; 305; 306; 308; 312; 314; 318; 323; 324; 325; 326; 330; 336; 337; 338; 339; 340; 341; 342; 343; 344; 347; 351; 353; 356; 359; 360; 361; 362; 363; 364; 371; 372; 374; 378; 380; 381; 382; 383; 384; 387; 388; 393; 397; 399; 402; 403; 408; 414; 415; 418; 420; 421; 422; 426; 428; 430; 433; 441; 446; 449; 457; 458; 460; 465; 471; 472; 473; 475; 476; 478; 480; 481; 482; 484; 485; 486; 490; 493; 494; 497; 501; 502; 504; 505; 509; 510; 514; 516; 520; 525; 526; 527; 528; 529; 530; 537; 538; 539; 541; 545; 546; 550; 559; 560; 561; 562; 564; 565; 571; 576; 577; 578; 580; 581; 584; 585; 586; 590; 591; 593; 594; 595; 596; 602; 607; 609; 612; 615; 624; 635; 639; 640; and 644.

8. The method of claim 1, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 38; 55; 66; 91; 93; 102; 103; 133; 142; 144; 153; 163; 190; 210; 232; 254; 280; 296; 300; 304; 311; 321; 335; 378; 383; 384; 420; 425; 429; 432; 468; 473; 487; 516; 519; 544; 553; 573; 577; 578; 585; 587; 589; 592; 605; 608; and 644, and wherein differential expression of genes associated with lymph node metastases in colon cancer is detected.

9. The method of claim 8, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 55; 66; 144; 153; 432; 553; and 608.

10. The method of claim 8, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 38; 91; 93; 102; 103; 133; 142; 163; 190; 210; 232; 254; 280; 296; 300; 304; 311; 321; 335; 378; 383; 384; 420; 425; 429; 468; 473; 487; 516; 519; 544; 573; 577; 578; 585; 587; 589; 592; 605; and 644.

11. The method of claim 1, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 29; 48; 56; 62; 71; 77; 82; 109; 112; 135; 136; 154; 157; 166; 167; 186; 220; 226; 236; 237; 239; 240; 242; 244; 253; 260; 277; 290; 297; 348; 358; 375; 376; 404; 407; 412; 416; 424; 431; 450; 451; 452; 462; 474; 477; 479; 486; 498; 511; 521; 533; 534; 535; 542; 572; 619; and 622, and wherein differential gene expression associated with MSI phenotype in colon cancer is detected.

12. The method of claim 11, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 48; 56; 62; 157; 186; 220; 226; 253; 260; 376; 450; 452; 462; 498; and 511.

13. The method of claim 11, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 29; 71; 77; 82; 109; 112; 135; 136; 154; 166; 167; 236; 237; 239; 240; 242; 244; 277; 290; 297; 348; 358; 375; 404; 407; 412; 416; 424; 431; 451; 474; 477; 479; 486; 521; 533; 534; 535; 542; 572; 619; and 622.

14. The method of claim 1, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 6; 19; 43; 49; 83; 89; 94; 100; 151; 168; 172; 177; 224; 252; 258; 265; 309; 315; 316; 320; 322; 328; 355; 365; 391; 443; 453; 455; 466; 483; 496; 499; 506; 512; 513; 515; 517; 531; 532; 554; 563; 575; 579; 606; 618; and 637, and wherein differential gene expression associated with the location of a primary colorectal carcinoma in colon cancer is detected.

15. The method of claim 14, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 19; 43; 89; 94; 100; 168; 224; 309; 328; 355; 391; 466; 531; 532; 563; and 637.

16. The method of claim 14, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 6; 49; 83; 151; 172; 177; 252; 258; 265; 315; 316; 320; 322; 365; 443; 453; 455; 483; 496; 499; 506; 512; 513; 515; 517; 554; 575; 579; 606; and 618.

17. The method of claim 1, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 2; 3; 5; 7; 8; 10; 12; 14; 20; 22; 23; 26; 28; 32; 33; 35; 36; 41; 42; 44; 47; 50; 51; 60; 61; 63; 64; 70; 73; 74; 81; 92; 93; 95; 106; 115; 118; 120; 121; 123; 129; 130; 132; 133; 137; 145; 148; 149; 160; 161; 162; 163; 183; 187; 188; 195; 199; 200; 202; 206; 209; 211; 213; 214; 217; 219; 222; 228; 229; 230; 233; 234; 238; 245; 246; 247; 250; 257; 269; 271; 274; 275; 276; 282; 283; 284; 285; 289; 291; 292; 296; 302; 303; 304; 312; 314; 318; 323; 327; 333; 334; 335; 336; 337; 339; 340; 341; 342; 344; 345; 347; 350; 351; 356; 359; 361; 362; 363; 364; 367; 370; 373; 374; 378; 380; 381; 382; 383; 384; 387; 389; 402; 403; 408; 411; 414; 418; 420; 428; 430; 433; 435; 439; 444; 446; 447; 449; 456; 457; 458; 460; 461; 465; 473; 478; 482; 484; 489; 490; 491; 494; 497; 501; 502; 504; 510; 514; 516; 520; 523; 528; 529; 530; 536; 537; 538; 539; 540; 548; 551; 556; 561; 562; 570; 571; 580; 581; 582; 584; 586; 590; 591; 593; 594; 596; 603; 607; 609; 612; 615; 620; 624; 625; 628; 635; 639; and 640, and wherein differential expression associated with the survival and death of subjects with colon cancer is detected.

18. The method of claim 17, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 5; 14; 36; 44; 61; 64; 70; 81; 95; 115; 121; 132; 183; 209; 228; 275; 333; 334; 350; 367; 373; 435; 439; 523; 570; 603; and 625.

19. The method of claim 17, wherein the predefined polynucleotide sequence sets are selected from the group consisting of: 2; 3; 7; 8; 10; 12; 20; 22; 23; 26; 28; 32; 33; 35; 41; 42; 47; 50; 51; 60; 63; 73; 74; 92; 93; 106; 118; 120; 123; 129; 130; 133; 137; 145; 148; 149; 160; 161; 162; 163; 187; 188; 195; 199; 200; 202; 206; 211; 213; 214; 217; 219; 222; 229; 230; 233; 234; 238; 245; 246; 247; 250; 257; 269; 271; 274; 276; 282; 283; 284; 285; 289; 291; 292; 296; 302; 303; 304; 312; 314; 318; 323; 327; 335; 336; 337; 339; 340; 341; 342; 344; 345; 347; 351; 356; 359; 361; 362; 363; 364; 370; 374; 378; 380; 381; 382; 383; 384; 387; 389; 402; 403; 408; 411; 414; 418; 420; 428; 430; 433; 444; 446; 447; 449; 456; 457; 458; 460; 461; 465; 473; 478; 482; 484; 489; 490; 491; 494; 497; 501; 502; 504; 510; 514; 516; 520; 528; 529; 530; 536; 537; 538; 539; 540; 548; 551; 556; 561; 562; 571; 580; 581; 582; 584; 586; 590; 591; 593; 594; 596; 607; 609; 612; 615; 620; 624; 628; 635; 639; and 640.

20. The method of claim 1, wherein the predefined polynucleotide sequence are 1; 4; 15; 21; 27; 58; 68; 75; 79; 95; 98; 101; 114; 119; 127; 131; 140; 155; 176; 192; 241; 243; 259; 263; 270; 279; 286; 298; 299; 307; 310; 312; 313; 317; 329; 346; 357; 360; 361; 394; 395; 398; 405; 406; 413; 427; 436; 437; 438; 443; 454; 464; 507; 522; 547; 552; 555; 568; 569; 614; 631; 634; 636; 641; and 644.

21. The method of claim 1 wherein the predefined polynucleotide sequence sets are 32; 33; 50; 133; 188; 217; 271; 284; 296; 303; 312; 323; 340; 343; 361; 403; 408; 473; 484; 494; 502; 516; and 624.

22. The method of claim 1, wherein the predefined polynucleotide sequence sets are 142; 144; 153; 190; 280; 468; 553; and 589.

23. The method of claim 1, wherein the predefined polynucleotide sequence sets are 29; 62; 71; 109; 136; 154; 348; 404; 412; 416; 431; 451; 479; 486; 498; 535 and 622.

24. The method of claim 1, wherein the predefined polynucleotide sequence sets are 109; 154; 412; 486; 535 and 622.

25. The method of claim 1, wherein the predefined polynucleotide sequence sets are 10; 12; 33; 214; 217; 271; 344; 383; 387; 414; 473; 484; 516; 536; and 561.

26. The method of claim 1, wherein the predefined polynucleotide sequence sets are 43; 100; 151; 172; 265; 315; 443; 499; 532 and 554.

27. The method of claim 1, wherein said detection of over expression or under expression of polynucleotide sequences is carried out by FISH or IHC.

28. The method of claim 1, wherein said detection is performed on nucleic acids from a tissue sample.

29. The method of claim 1, wherein said detection is performed on nucleic acids from a tumor cell line.

30. The method of claim 1, wherein said detection is performed on DNA microarrays.

31. A method or prognosis or diagnosis of colon cancer, or for monitoring the treatment of a subject with a colon cancer, comprising: 1) obtaining colon tissue polynucleotide sequences from a subject; and 2) analyzing the colon tissue polynucleotide sequences by detecting the overexpression or underexpression of a pool of polynucleotide sequences, said pool comprising all or part of the polynucleotide sequences, or subsequences or complements thereof, selected from each of predefined polynucleotide sequnce sets 1 through 644.

32. A method for differentiating a normal cell from a cancer cell, comprising: 1) obtaining polynucleotide sequences from normal and cancer cells; and 2) analyzing the polynucleotide sequences from step 1) by detecting the overexpression or underexpression of a pool of polynucleotide sequences, said pool comprising all or part of the polynucleotide sequences, or subsequences or complements thereof, selected from each of predefined polynucleotide sequnce sets 1 through 644.

33. A polynucleotide library, comprising a pool of polynucleotide sequences either overexpressed or underexpressed in colon tissue or cells, said pool corresponding to all or part of the polynucleotide sequences of SEQ ID Nos. 1 through 1596, or subsequences or complements thereof.

34. A polynucleotide library according to claim 33, immobilized on a solid support.

35. A polynucleotide library according to claim 34, wherein the solid support is selected from the group consisting of nylon membrane, nitrocellulose membrane, glass slide, glass beads, membranes on glass support and silicon chip.

36. A method of detecting differential gene expression, comprising: 1) obtaining a test sample comprising polynucleotide sequences from a subject, 2) reacting the test sample obtained in step (1) with a polynucleotide library according to claim 33, and 3) detecting the reaction product of step (2).

37. The method of claim 36, wherein the test sample is labeled before reaction step (2).

38. The method of claim 37, wherein the label is selected from the group consisting of radioactive, calorimetric, enzymatic, molecular amplification, bioluminescent and fluorescent labels.

39. The method of claim 36, further comprising: 4) obtaining a control sample comprising polynucleotide sequences; 5) reacting the control sample with said polynucleotide library; 6) detecting a control sample reaction product; and 7) comparing the amount of the test sample reaction product to the amount of the control sample reaction product.

40. The method of claim 36, wherein the test sample comprises cDNA, RNA or mRNA.

41. The method of claim 40, wherein mRNA is isolated from the test sample and cDNA is obtained by reverse transcription of said mRNA.

42. The method of claim 36, wherein said reaction step is performed by hybridizing the test sample with the polynucleotide library.

43. The method of claim 36, wherein conditions associated with colorectal cancer are detected, diagnosed, staged, classified, monitored, predicted, prevented or treated.

44. A method of assigning a therapeutic regimen to subject who has histopathological features of colorectal disease, comprising: 1) detecting the overexpression or underexpression of a pool of polynucleotide sequences from colon tissues, said pool comprising all or part of the polynucleotide sequences, or subsequences or complements thereof, selected from each of predefined polynucleotide sequence sets 1 through 644; 2) classifying said subject as having a “poor prognosis” or a “good prognosis” on the basis of the the overexpression or underexpression detected in step (1); 3) assigning said subject a therapeutic regimen, said therapeutic regimen (i) comprising no adjuvant chemotherapy if the patient is lymph node negative and is classified as having a good prognosis, or (ii) comprising chemotherapy if said patient has any other combination of lymph node status and expression profile.

45. The method of claim 44, wherein the assigning of a therapeutic regimen comprises the use of an appropriate dose of irinotecan.

46. The method of claim 45, wherein the dose of irinotecan is selected according to the presence or the absence of a polymorphism in a uridine diphosphate glucuronosyltransferase I (UGT1A1) gene promoter of the subject.

47. The method of claim 46, wherein the polymorphism is the presence of an abnormal number of (TA) repeats in the sequence of said promoter.