Human nucleic acid sequences which are overexpressed in normal pancreas tissue

[0001] The invention relates to human nucleic acid sequences from normal pancreatic tissue, which code for gene products or portions thereof, their functional genes that code at least one bioactive polypeptide and their use.

[0002] In addition, the invention relates to the polypeptides that can be obtained by way of the sequences and their use.

[0003] One of the main causes of death is the pancreatic tumor, for control of which new therapies are necessary. Previously used therapies, such as, e.g., chemotherapy, hormone therapy or surgical removal of tumor tissue, frequently do not result in a complete cure.

[0004] The cancer phenomenon often goes along with overexpression or underexpression of certain genes in degenerated cells, it still being unclear whether these altered expression rates are the cause or the result of the malignant transformation. Identification of these genes would be an important step for development of new therapies against cancer. Spontaneous formation of cancer is often preceded by a host of mutations. They can have the most varied effects on the expression pattern in the affected tissue, such as, e.g., underexpression or overexpression, but also expression of shortened genes. Several such changes due to these mutation cascades can ultimately lead to malignant degeneration. The complexity of these relationships makes an experimental approach very difficult.

[0005] A database that consists of so-called ESTs is used to look for candidate genes, i.e., genes that compared to the tumor tissue are more strongly expressed-in normal tissue. ESTs (expressed sequence tags) are sequences of cDNAs, i.e., mRNAs transcribed in reverse, therefore molecules that reflect gene expression. The EST sequences are determined for normal and degenerated tissue. These databases are offered to some extent commercially by various companies. The ESTs of the LifeSeq database, which is used here, are generally between 150 and 350 nucleotides long. They represent a pattern that is unmistakable for a certain gene, although this gene is normally very much longer (>2000 nucleotides). By comparison of the expression patterns of normal and tumor tissue, ESTs can be identified that are important for tumor formation and proliferation. There is, however, the following problem: Since the EST sequences that are found can belong to different regions of an unknown gene due to different constructions of cDNA libraries, in this case a completely incorrect ratio of the occurrence of these ESTs in the respective tissue would arise. This would only be noticed when the complete gene is known and thus ESTs can be assigned to the same gene.

[0006] It has now been found that this error possibility can be reduced if all ESTs from the respective tissue type are assembled beforehand, before the expression patterns are compared to one another. Overlapping ESTs of the same gene were thus combined into longer sequences (see FIG. 1, FIG. 2a and FIG. 3). This lengthening and thus coverage of an essentially larger gene, region in each of the respective bases are intended to largely avoid the above-described error. Since there were no existing software products for this purpose, programs for assembling genomic sections were employed, which were used modified and to which our own programs were added. A flow chart of the assembly procedure is shown in FIGS. 2b1-2b4.

[0007] Nucleic acid sequences Seq. ID Nos. 2-37, and 67, which play a role as candidate genes in the pancreatic tumor, have now been found.

[0008] Nucleic acid sequences Seq. ID Nos. 14, 24, 25, 27-31, 35-37 and 67 are of special interest.

[0009] The invention thus relates to nucleic acid sequences that code a gene product or a portion thereof, comprising

[0010] a) a nucleic acid sequence selected from the group of nucleic acid sequences Seq. ID Nos. 14, 24, 25, 27-31, 35-37, and 67,

[0011] b) an allelic variation of the nucleic acid sequences named under a)

[0012] or

[0013] c) a nucleic acid sequence that is complementary to the nucleic acid sequences named under a) or b).

[0014] In addition, the invention relates to a nucleic acid sequence according to one of the sequences Seq. ID Nos. 14, 24, 25, 27-31, 35-37, 67 or a complementary or allelic variant thereof and the nucleic acid sequences thereof, which have 90% to 95% homology to a human nucleic acid sequence.

[0015] The invention also relates to nucleic acid sequences Seq. ID Nos. 2-37, and 67 which-are expressed elevated in normal pancreatic tissue.

[0016] The invention further relates to nucleic acid sequences comprising a portion of the above-mentioned nucleic acid sequences in such a sufficient amount that they hybridize with sequences Seq. ID Nos. 14, 24, 25, 27-31, 35-37, and 67.

[0017] The nucleic acid sequences according to the invention generally have a length of at least 50 to 4500 bp, preferably a length of at least 150 to 4000 bp, especially a length of 450 to 3500 bp.

[0018] With the partial sequences Seq. ID Nos. 2-37 and 67 according to the invention, expression cassettes can also be built using current process practice, whereby on the cassette at least one of the nucleic acid sequences according to the invention is combined with at least one control or regulatory sequence generally known to one skilled in the art, such as, e.g., a suitable promoter. The sequences according to the invention can be inserted in a sense or antisense orientation.

[0019] A large number of expression cassettes or vectors and promoters which can be used are known in the literature.

[0020] Expression cassettes or vectors are defined as:

[0021] 1. bacterial, such as, e.g., phagescript, pBs, φX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene), pTrc99A, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia), 2. eukaryotic, such as, e.g., pWLneo, pSV2cat, pOG44, pXT1, pSG (Stratagene), pSVK3, pBPV, pMSG, pSVL (Pharmacia).

[0022] A control or regulatory sequence is defined as suitable promoters. Here, two preferred vectors are the pKK232-8 and the PCM7 vector. In particular, the following promoters are intended: lacI, lacZ, T3, T7, gpt, lambda PR, trc, CMV, HSV thymidine-kinase, SV40, LTRs from retrovirus and mouse metallothionein-I.

[0023] The DNA sequences located on the expression cassette can code a fusion protein which comprises a known protein and a bioactive polypeptide fragment.

[0024] The expression cassettes are likewise the subject matter of this invention.

[0025] The nucleic acid fragments according to the invention can be used to produce full-length genes. The genes that can be obtained are likewise the subject matter of this invention.

[0026] The invention also relates to the use of the nucleic acid sequences according to the invention and the gene fragments that can be obtained from use.

[0027] The nucleic acid sequences according to the invention can be moved with suitable vectors into host cells, in which as the heterologous part, the genetic information which is contained on the nucleic acid fragments and which is expressed is located.

[0028] The host cells containing the nucleic acid fragments are likewise the subject matter of this invention.

[0029] Suitable host cells are, e.g., prokaryotic cell systems such as E. coli or eukaryotic cell systems such as animal or human cells or yeasts.

[0030] The nucleic acid sequences according to the invention can be used in the sense or antisense form.

[0031] Production of polypeptides or their fragments is done by cultivation of the host cells according to current cultivation methods and subsequent isolation and purification of the peptides or fragments, likewise using current methods. The invention further relates to nucleic acid sequences, which code at least a partial sequence of a bioactive polypeptide.

[0032] This invention further relates to polypeptide partial sequences, so-called ORF (open-reading-frame)-peptides, according to the sequence protocols Seq. ID Nos. 39-63 and 68-71.

[0033] The invention further relates to the polypeptide sequences that have at least 80% homology, especially 90% homology to the polypeptide partial sequences of Seq. ID Nos. 39-63 and 68-71 according to the invention.

[0034] The invention also relates to antibodies that are directed against a polypeptide or a fragment thereof and that are coded by the nucleic acids of sequences Seq. ID Nos. 2-37 and 67.

[0035] Antibodies are defined especially as monoclonal antibodies.

[0036] The antibodies according to the invention can be identified by, i.a., a phage display process. These antibodies are also the subject matter of the invention.

[0037] The polypeptide partial sequences according to the invention can be used in a phase display process. The polypeptides that are identified with this process and that bind to the polypeptide partial sequences according to the invention are also the subject matter of the invention.

[0038] The nucleic acid sequences according to the invention can also be used in a phage display process.

[0039] The polypeptides of sequences Seq. ID Nos. 39-63 and 68-71 according to the invention can also be used as tools for finding active ingredients against pancreatic tumors, which is likewise the subject matter of this invention.

[0040] Likewise the subject matter of this invention is the use of nucleic acid sequences according to sequences Seq. ID Nos. 2-37 and 67 for expression of polypeptides, which can be used as tools for finding active ingredients against pancreatic tumors.

[0041] The invention also relates to the use of the founds polypeptide partial sequences Seq. ID Nos. 39-63 and 68-71 as pharmaceutical agents in the gene therapy for treatment of pancreatic tumors or for the production of a pharmaceutical agent for treatment of pancreatic tumors.

[0042] The invention also relates to pharmaceutical agents that contain at least one polypeptide partial sequence Seq. ID Nos. 39-63 and 68-71.

[0043] The nucleic acid sequences found according to the invention can also be genomic or mRNA sequences.

[0044] The invention also relates to genomic genes, their exon and intron structures and their splice variants that can be obtained from cDNAs of sequences Seq. ID Nos. 2-37 and 67, and their use together with suitable regulatory elements, such as suitable promoters and/or enhancers.

[0045] With the nucleic acids according to the invention (cDNA sequences) Seq. ID Nos. 2-37 and 67, genomic BAC, PAC and cosmid libraries are screened, and specifically human clones are isolated via complementary base pairing (hybridization). The BAC, PAC and cosmid clones isolated in this way are hybridized using fluorescence-in-situ hybridization on metaphase chromosomes, and the corresponding chromosome sections on which the corresponding genomic genes lie are identified. BAC, PAC and cosmid clones are sequenced in order to clarify the corresponding genomic genes in their complete structure (promoters, enhancers, silencers, exons and introns). BAC, PAC and cosmid clones can be used as independent molecules for gene transfer (see FIG. 5).

[0046] The invention also relates to BAC, PAC and cosmid clones containing functional genes and their chromosomal localization according to sequences Seq. ID Nos. 2-37 and 67, for use as vehicles for gene transfer.

[0047] Meanings of Technical Terms and Abbreviations

[0048] Nucleic acids=Nucleic acids in this invention are defined as: mRNA, partial cDNA, full-length cDNA and genomic genes (chromosomes)

[0049] ORF=Open Reading Frame, a defined sequence of amino acids which can be derived from the cDNA sequence

[0050] Contig=A set of DNA sequences that can be combined as a result of very great similarities into one sequence (consensus)

[0051] Singleton=A contig that contains only one sequence

[0052] Module=Domain of a protein with a defined sequence, which represents one structural unit and which occurs in various proteins

[0053] N=selectively the nucleotide A, T, G or C

[0054] X=selectively one of the 20 naturally occurring amino acids

[0055] Explanation of the Alignment Parameters

[0056] minimal initial match=minimal initial identity area

[0057] maximum pads per read=maximum number of insertions

[0058] maximum percent mismatch=maximum deviation in %

EXPLANATION OF FIGURES

[0059]
FIG. 1 shows the systematic gene search in the Incyte LifeSeq database

[0060]

FIG. 2

a
shows the principle of EST assembling

[0061]

FIGS. 2

b

1
-2b4 show the entire principle of EST assembling

[0062]
FIG. 3 shows the in-silico subtraction of gene expression in various tissues

[0063]

FIG. 4

a
shows the determination of tissue-specific expression via electronic Northern

[0064]

FIG. 4

b
shows the electronic Northern

[0065]
FIG. 5 shows the isolation of genomic BAC and PAC clones.

[0066] The following examples explain the production of the nucleic acid sequences according to the invention without limiting the invention to these examples and nucleic acid sequences.

EXAMPLE 1

[0067] Search for Tumor-Related Candidate Genes

[0068] First, all ESTs of the corresponding tissue from the LifeSeq database (from October 1997) were extracted. They were then assembled by means of the GAP4 program of the Staden package with the parameters 0% mismatch, 8 pads per read and a minimal match of 20. The sequences (fails) not recorded in the GAP4 database were assembled first at 1% mismatch and then again at 2% mismatch with the database. Consensus sequences were computed from the contigs of the database that consisted of more than one sequence. The singletons of the database, which consisted of only one sequence, were re-assembled at 2% mismatch with the sequences not recorded in the GAP4 database. In turn, the consensus sequences were determined for the contigs. All other ESTs were re-assembled at 4% mismatch. The consensus sequences were extracted once again and finally assembled with the previous consensus sequences and the singletons and the sequences not recorded in the database at 4% mismatch. The consensus sequences were formed and used with the singletons and fails as the initial basis for tissue comparisons. This procedure ensured that among the parameters used, all sequences represented gene regions independent of one another.

[0069]

FIGS. 2

b

1
-2b4 illustrate the lengthening of the normal pancreatic tissue ESTs.

[0070] The sequences of the respective tissue assembled in this way were then compared to one another by means of the same program (FIG. 3). To do this, first all sequences of the first tissue were input into the database. (It was therefore important that they were independent of one another).

[0071] Then, all sequences of the second tissue were compared to all those of the first. The result was sequences that were specific to the first or the second tissue as well as those which occurred in both. In the latter, the ratio of the frequency of occurrence in the respective tissue was evaluated. All programs pertaining to the evaluation of the assembled sequences were themselves developed.

[0072] All sequences that occurred more than four times in respectively one of the compared tissues and all that occurred at least five times as often in one of the two tissues were further studied. These sequences were subjected to an electronic Northern (see Example 2.1), by which the distribution in all tumor and normal tissues was studied (see FIG. 4a and FIG. 4b). The relevant candidates were then lengthened using all Incyte ESTs and all ESTs of public databases (see Example 3). Then, the sequences and their translation into possible proteins were compared to all nucleotide and protein databases and were studied for possible regions that code for proteins.

EXAMPLE 2

[0073] Algorithm for Identification and Lengthening of Partial cDNA Sequences with Altered Expression Pattern

[0074] An algorithm for finding overexpressed or underexpressed genes will be explained below. The individual steps are also summarized in a flow chart for the sake of clarity (see FIG. 4b).

[0075] 2.1. Electronic Northern Blot

[0076] By means of a standard program for homology search, e.g., BLAST (Altschul, S. F.; Gish, W.; Miller, W.; Myers, E. W. and Lipman, D. J. (1990) J. Mol. Biol. 215, 403-410), BLAST2 (Altschul, S. F.; Madden, T. L.; Schaffer, A. A.; Zhang, J.; Zhang, Z.; Miller, W., and Lipman, D. J. (1997) Nucleic Acids Research 25 3389-3402) or FASTA (Pearson, W. R. and Lipman, D. J. (1988) Proc. Natl. Acad. Sci. USA 85 2444-2448), the homologous sequences in various EST libraries (private or public) arranged by tissues are determined for a partial DNA sequence S, e.g., an individual EST or a contig of ESTs. The (relative or absolute) tissue-specific occurrence frequencies of this partial sequence S which were determined in this way are called electronic Northern Blots.

[0077] 2.1.1

[0078] Analogously to the procedure described under 2.1, the sequence Seq. ID No. 2 was found, which occurs 9× more frequently in normal pancreatic tissue than in tumor tissue.

[0079] The result is as follows:

1Electronic Northern for SEQ. ID NO.: 2NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.00260.0000undefBreast0.00000.0000undefundefSmall intestine0.15020.01659.08310.1101Ovary0.00300.00261.15130.8686Endocrine tissue0.00000.0000undefundefGastrointestinal0.09390.009310.1472 0.0985Brain0.00000.00100.0000undefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00950.01940.49022.0400Heart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.15330.0000undefMuscle-skeleton0.00000.0000undefundefKidney0.00000.00680.0000undefPancreas2.74900.30379.05060.1105Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0611Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0039Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.1953Heart-blood vessels0.0036Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000

[0080] In an analogous procedure, the following Northerns were also found:

2Electronic Northern for SEQ. ID NO.: 4NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00310.0000undef0.0000Ovary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00380.0000undef0.0000Brain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00270.00680.39652.5219Pancreas0.13550.01668.17670.1223Penis0.00000.0000undefundefProstate0.00000.00210.0000undefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0028Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 6NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0026 0.0000undefBreast0.00000.0000undefundefSmall intestine0.00310.0000undef0.0000Ovary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00620.0000undef0.0000Stomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.80780.016648.76110.0205Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0139Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 7NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00310.0000undef0.0000Ovary0.00000.0000undefundefEndocrine tissue0.00000.3310 0.0000undefGastrointestinal0.00190.0000undef0.0000Brain0.00890.0051 1.72790.5787Hematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.09910.005517.94890.0557Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0389Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0006Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0110Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 9NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.18670.0000undef0.0000Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0000Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0244Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0154Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 11NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0128 0.0000undefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00600.0234 0.25583.9088Endocrine tissue0.00000.0000undefundefGastrointestinal0.00960.0000undef0.0000Brain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.01900.0000undef0.0000Heart0.00110.0000undef0.0000Testicles0.00000.0000undefundefLung0.00000.0020 0.0000undefStomach-esophagus0.00970.0077 1.26050.7933Muscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.41800.005575.68430.0132Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0009Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0944Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0164Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 12NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0051 0.0000undefBreast0.00000.0075 0.0000undefSmall intestine0.00610.0000undef0.0000Ovary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0041 0.0000undefHematopoietic0.00270.0000undef0.0000Skin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00320.0000undef0.0000Testicles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas3.84920.270614.22480.0703Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0009Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.2305Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0039Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.4149Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 14NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.01820.0000undef0.0000Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0028Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 15NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0038 0.0000undefSmall intestine0.00610.0000undef0.0000Ovary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0051 0.0000undefHematopoietic0.00400.0000undef0.0000Skin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00110.0000undef0.0000Testicles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas2.88610.287210.05020.0995Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0009Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.2777Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0039Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0854Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 16NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0026 0.0000undefBreast0.00000.0000undefundefSmall intestine0.00610.0000undef0.0000Ovary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0051 0.0000undefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00110.0000undef0.0000Testicles0.00000.0000undefundefLung0.00100.0000undef0.0000Stomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0068 0.0000undefPancreas1.52320.0110137.90700.0073Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.6386Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0197Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 17NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0051 0.0000undefBreast0.00000.0056 0.0000undefSmall intestine0.00000.0000undefundefOvary0.00000.0026 0.0000undefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0041 0.0000undefHematopoietic0.00270.0000undef0.0000Skin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00100.0000undef0.0000Stomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.92180.038723.84630.0419Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.1111Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0157Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 18NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0026 0.0000undefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00300.0000undef0.0000Endocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0010 0.0000undefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00540.0000undef0.0000Pancreas0.46590.022121.08990.0474Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0030Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0305Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0039Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 19NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.03140.0000undef0.0000Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0000Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0366Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 21NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.00260.0000undefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.15860.0000undef0.0000Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0000Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0057Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 24NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.00500.0000undefGastrointestinal0.00000.0000undefundefBrain0.00070.0000undef0.0000Hematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.02480.0000undef0.0000Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0030Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0056Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0122Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0010Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 25NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0019 0.0000undefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.22630.005540.98320.0244Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0528Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 27NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.03800.00556.88040.1453Pancreas0.00000.0000undefundefPenis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0000Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 28NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.04460.0000undef0.0000Pancreas0.00000.0000undefundefPenis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0056Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 29NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.02480.0000undef0.0000Pancreas0.00000.0000undefundefPenis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0000Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.1220Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 30NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0026 0.0000undefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undef0.0000Hematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.26930.011024.38050.0410Pancreas0.00000.0000undefundefPenis0.00220.0000undef0.0000Prostate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0028Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0010Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 31NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00130.0000undef0.0000Skin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.18500.011016.75230.0597Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.0000Breast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0000Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0061Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 35NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.03800.0000undef0.0000Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment00000Breast0.0000Gastrointestinal0.0083Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 36NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0026 0.0000undefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.33540.016620.24230.0494Penis0.00000.0000undefundefProstate0.00220.0000undef0.0000Uterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0028Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for SEQ. ID NO.: 37NORMALTUMORRatios% frequency% frequencyN/TT/NBladder0.00000.0000undefundefBreast0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefGastrointestinal0.00000.0000undefundefBrain0.00000.0000undefundefHematopoietic0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.01980.0000undef0.0000Penis0.00000.0000undefundefProstate0.00000.0000undefundefUterus-endometrium0.00000.0000undefundefUterus-myometrium0.00000.0000undefundefUterus-general0.00000.0000undefundefBreast hyperplasia0.0000Prostate hyperplasia0.0000Seminal vesicle0.0000Sensory organs0.0000White blood cells0.0000Cervix0.0000STANDARDIZED/SUBTRACTEDFETUSLIBRARIES% frequency% frequencyDevelopment0.0000Breast0.0000Gastrointestinal0.0000Ovary_n0.0000Brain0.0000Ovary_t0.0000Hematopoietic0.0000Endocrine tissue0.0000Skin0.0000Fetal0.0000Hepatic0.0000Gastrointestinal0.0000Heart-blood vessels0.0000Hematopoietic0.0000Lung0.0000Skin-muscle0.0000Suprarenal gland0.0000Testicles0.0000Kidney0.0000Lung0.0000Placenta0.0000Nerves0.0000Prostate0.0000Prostate0.0000Sensory organs0.0000Sensory Organs0.0000Uterus_n0.0000Electronic Northern for Seq. ID: 67NORMALTUMORRatios% frequency% frequencyN/TT/NB lymphoma0.00000.0000undefundefBladder0.00000.0000undefundefBreast0.00000.0000undefundefLarge intestine0.00000.0000undefundefSmall intestine0.00000.0000undefundefOvary0.00000.0000undefundefEndocrine tissue0.00000.0000undefundefBrain0.00000.0000undefundefSkin0.00000.0000undefundefHepatic0.00000.0000undefundefHeart0.00000.0000undefundefTesticles0.00000.0000undefundefLung0.00000.0000undefundefStomach-esophagus0.00000.0000undefundefMuscle-skeleton0.00000.0000undefundefKidney0.00000.0000undefundefPancreas0.19990.005536.19780.0276Prostate0.00000.0013 0.0000undefT lymphoma0.00510.0000undef0.0000Uterus0.00000.0000undefundefWhite blood cells0.00140.0000undef0.0000Hematopoietic0.0000Penis0.0000Seminal vescicle0.0000Sensory organs0.0000FETUS% freq.Development0.0000Gastrointestinal0.0000Brain0.0000Hematopoietic0.0000Skin0.0000Hepatic0.0000Heart-blood vessels0.0000Lung0.0000Adrenal gland0.0000Kidney0.0000Placenta0.0000Prostate0.0000Sensory organs0.0000STANDARDIZED/SUBTRACTEDLIBRARIES % frequencyBreast0.0000Breast_t0.0000Large Intestine_t0.0000Ovary_n0.0000Ovary_t0.0000Endocrine tissue0.0000Fetal0.0000Gastrointestinal0.0244Hematopoietic0.0000Skin-muscle0.0000Testicles_n0.0000Testicles_t0.0000Lungs_n0.0000Lungs_t0.0000Nerves0.0000Kidney_t0.0000Ovary_uterus0.0000Prostate_n0.0000Sensory organs0.0000White blood cells0.0000

[0081] 2.2. Fisher Test

[0082] In order to decide whether a partial sequence S of a gene occurs significantly more often or less often in a library for normal tissue than in a library for degenerated tissue, Fisher's exact test, a standard statistical process, is carried out (Hays, W. L., (1991) Statistics, Harcourt Brace College Publishers, Fort Worth).

[0083] The null hypothesis reads: The two libraries cannot be distinguished with respect to the frequency of sequences homologous to S. If the null hypothesis can be rejected with high enough certainty, the gene belonging to S is accepted as an advantageous candidate for a cancer gene, and in the next step an attempt is made to achieve lengthening of its sequence.

EXAMPLE 3

[0084] Automatic Lengthening of the Partial Sequence

[0085] Automatic lengthening of partial sequence S is completed in three steps:

[0086] 1. Determination of all sequences homologous to S from the total set of available sequences using BLAST

[0087] 2. Assembling these sequences by means of the standard program GAP4 (Bonfield, J. K.; Smith, K. F. and Staden, R. (1995), Nucleic Acids Research 23 4992-4999) (contig formation).

[0088] 3. Computation of a consensus sequence C from the assembled sequences.

[0089] Consensus sequence C will generally be longer than initial sequence S. Its electronic Northern Blot will accordingly deviate from that for S. A repeated Fisher test decides whether the alternative hypothesis of deviation from a uniform expression in the two libraries can be maintained. If this is the case, an attempt is made to lengthen C in the same way as S. This iteration is continued with consensus sequences Ci (i: iteration index) obtained in each case until the alternative hypothesis is rejected (if H0 Exit; truncation criterion I) or until automatic lengthening is no longer possible (while Ci>Ci−1; truncation criterion II)

[0090] In the case of truncation criterion II, with the consensus sequence present after the last iteration, a complete or roughly complete sequence of a gene which can be related to cancer with high statistical certainty is acquired.

[0091] Analogously to the above-described examples, it was possible to find from normal pancreatic tissue the nucleic acid sequences described in Table I.

[0092] Furthermore, for the individual nucleic acid sequences, it was possible to determine the peptide sequences (ORFs) that are listed in Table II, in which no peptide can be assigned to a few nucleic acid sequences and more than one peptide can be assigned to some nucleic acid sequences. As already mentioned above, both the determined nucleic acid sequences and the peptide sequences assigned to the nucleic acid sequences are the subject of this invention.

EXAMPLE 4

[0093] Mapping of Nucleic Acid Sequences on the Human Genome

[0094] Human genes were mapped using the Stanford G3 Hybrid Panel (Stewart et al., 1997), which is marketed by Research Genetics, Huntsville, Ala. This panel consists of 83 different genomic DNAs of human-hamster hybrid cell lines and allows resolution of 500 kilobases. The hybrid cell lines were obtained by fusion of irradiated diploid human cells with cells of the Chinese hamster. The retention pattern of the human chromosome fragments is determined by means of gene-specific primers in a polymerase chain reaction and is analyzed using software available from the Stanford RH server (http://www.stanford.edu/RH/rhserver_form2.html). This program determines the STS marker that is nearest to the desired gene. The corresponding cytogenetic band was determined using the “Mapview” program of the Genome Database (GDB), (http://gdbwww.dkfz-heidelberg.de).

[0095] In addition to mapping of genes on the human chromosome set by various experimental methods, it is possible to determine the location of genes on this by biocomputer methods. To do this, the known program e-PCR was used (Schuler GD (1998) Electronic PCR: Bridging the gap between genome mapping and genome sequencing. Trends Biotechnol 16: 456-459, Schuler GD (1997). Sequence mapping by electronic PCR. Genome Res. 7: 541-550). The database used here no longer corresponds to the one cited in the literature, but is a further development which includes data from the public database RHdb (http://www.ebi.ac.uk/RHdb/-index.html). Analogously to the mapping by the hybrid panels, the results were evaluated with the above-mentioned software and the software of the Whitehead-Institute (http://carbon.wi.mit.edu:8000/cgi-bin/contig/rhmapper.p1).

EXAMPLE 5

[0096] Obtaining Genomic DNA Sequences (BAC Clones)

[0097] The genomic BAC clones that contain the corresponding cDNAs (http://www.tree.caltech.edu/; Shizuya, H.; B. Birren, U -J. Kim, V. Mancino, T. Slepak, Y. Tachiiri, M. Simon (1992) Proc. Natl. Acad. Sci., USA 89: 8794-8797) were isolated with the procedure of “down-to-the-well”. In this procedure, a library consisting of BAC clones (the library covers roughly 3× the human genome) is moved into a certain raster, so that the DNA of these clones with a specific PCR can be studied. In doing so, “pooling” of the DNA of different BAC clones takes place. Combinatorial analysis makes it possible to determine the clones that contain the desired DNA. By fixing the clones, the address of the clones in the library can be determined. This address together with the name of the library which is being used unequivocally fixes the clones and thus the DNA sequence of these clones.

3TABLE ICol. 1Seq. ID No.Col. 2ExpresssionCol. 3FunctionCol. 4ModulesCol. 5Cytogenetic localizationCol. 6Nearest marker

[0098]

4

TABLE I

Seq.

ID

No.
Expression
Function

2
Overexpressed in normal
Human mRNA for

pancreatic tissue
regenerating protein I

beta

4
Overexpressed in normal
Glandular kallikrein 1

pancreatic tissue

6
Overexpressed in normal
cDNA encoding human

pancreatic tissue
phospholipase A2

7
Overexpressed in normal
Human somatostatin I

pancreatic tissue

9
Overexpressed in normal
Human islet amyloid

pancreatic tissue
protein

11
Overexpressed in normal
Human pancreatic secretory

pancreatic tissue
trypsin inhibitor (PSTI)

12
Overexpressed in normal
Human protease E

pancreatic tissue

14
Overexpressed in normal
Homolog to trypsin

pancreatic tissue
precursor

15
Overexpressed in normal
Human chymotrypsinogen

pancreatic tissue

16
Overexpressed in normal

Homo sapiens
colipase

pancreatic tissue
(CLPS)

17
Overexpressed in normal
caldecrin = serum calcium-

pancreatic tissue
decreasing factor

18
Overexpressed in normal
Human pancreatic zymogen

pancreatic tissue
granule membrane protein

GP-2

19
Overexpressed in normal
Human IAPP

pancreatic tissue

21
Overexpressed in normal

H. sapiens
mRNA for

pancreatic tissue
chymotrypsin-like protease

CTRL-1

24
Overexpressed in normal
Human homolog to D.

pancreatic tissue
melanogaster Calbindin-32

25
Overexpressed in normal
Human homolog to R.

pancreatic tissue

norvegicus
syncollin

27
Overexpressed in normal

Mus musculus
unknown

pancreatic tissue
protein precursor

28
Overexpressed in normal
Unknown

pancreatic tissue

29
Overexpressed in normal
Unknown

pancreatic tissue

30
Overexpressed in normal
Unknown

pancreatic tissue

31
Overexpressed in normal
Unknown

pancreatic tissue

35
Overexpressed in normal
Unknown

pancreatic tissue

36
Overexpressed in normal
Unknown

pancreatic tissue

37
Overexpressed in normal
Unknown

pancreatic tissue

67
Overexpressed in normal
Lengthening to Sequence

pancreatic tissue
ID: 27

[0099]

5

TABLE I

Cytogenetische

Seq ID No.
Expression
Funktion
Module
Lokalisation
Nächster Marker

2
in Pankreasnormalgewebe
Human mRNA for regenerating protein I beta
C_TYPE—
2p13.1
CHLC.GCT1B4

überexprimiert

LECTIN_2

4
in Pankreasnormalgewebe
Glanduläres Kallikrein 1
trypsin

überexprimiert

6
in Pankreasnormalgewebe
cDNA encoding human phospholipase A2
phoslip
12q24.22-q24.23
SHGC-10488-

überexprimiert

AFMa225xe5

7
in Pankreasnormalgewebe
Human somalostatin I

3q26.33-q28
D3S1262-D3S1580

überexprimiert

9
in Pankreasnormalgewebe
Human islet amyloid protein
Calc_CGRP_I
12p12.3-p12.2
D12S364-D12S310

überexprimiert

APP

11
in Pankreasnormalgewebe
Human pancreatic secretory trypsin inhibitor
kazal
12p12.3
WI-7377-D12S1669

überexprimiert
(PSTI)

12
in Pankreasnormalgewebe
Human protease E
trypsin

überexprimiert

14
in Pankreasnormalgewebe
Homolog zu Trypsin precursor

überexprimiert

15
in Pankreasnormalgewebe
Humanes Chymotrypsinogen
TRYPSIN—
16q24.1-q24.2
CHLC:GATA71F09

überexprimiert

CATAL

16
in Pankreasnormalgewebe

Homo sapiens
colipase (CLPS)
Colipase
6p21.2-p21.31
D6S439-D6S291

überexprimiert

17
in Pankreasnormalgewebe
caldecrin = serum calcium-decreasing factor
TRYPSIN—
1p36.13
AFMa127zc9-

überexprimiert

CATAL

AFMa232zb9

18
in Pankreasnormalgewebe
Human pancreatic zymogen granule membrane
zona_pellucida
16p11.2
WI-3768

überexprimiert
protein GP-2

19
in Pankreasnormalgewebe
Humanes IAPP
71m_2
12p12.3
WI-7377-D12S1669

überexprimiert

21
in Pankreasnormalgewebe

H. sapiens
mRNA for chymotrypsin-like
PRO_RICH
16q22.3-q23.1
WI-9392

überexprimiert
protease CTRL-1

24
in Pankreasnormalgewebe
Humanes Homolog zu D. melanogasler
EF_HAND_2

überexprimiert
Calbindin-32

25
in Pankreasnormalgewebe
Humanes Homolog zu R. norvegicus syncollin

19q13.2
SHGC-8810-SHGC-

überexprimiert

37129

27
in Pankreasnormalgewebe

Mus musculus
unknown protein precursor
CUB; zona—

überexprimiert

pellucida

28
in Pankreasnormalgewebe
unbekannt

überexprimiert

29
in Pankreasnormalgewebe
unbekannt

16p12.3-p12.2
D16S3045-SHGC-

überexprimiert

6042

30
in Pankreasnormalgewebe
unbekannt

16p12.3-p12.2
D16S3045-SHGC-

überexprimiert

6042

31
in Pankreasnormalgewebe
unbekannt
trypsin
16q23.1
SHGC-14629-

überexprimiert

SHGC-8141

35
in Pankreasnormalgewebe
unbekannt
PRO_RICH
7q32.3-q33
SHGC-30423-

überexprimiert

AFM183xe11

36
in Pankreasnormalgewebe
unbekannt
PRO_RICH
16p12.3-p12.2
D16S3045-SHGC-

überexprimiert

6042

37
in Pankreasnormalgewebe
unbekannt

10q25.1-q25.3
AFM249vf1-SHGC-

überexprimiert

14812

67
in Pankreasnormalgewebe
Verlängerung zu Seq ID: 27

überexprimiert

[0100]

6

TABLE II

DNA Seq. ID. No.:
Peptide Seq. ID. No.:

DNA Seq ID No:
Peptid Seq ID No:

14
68

69

24
39

40

25
41

42

43

27
44

28
45

29
46

30
47

48

49

31
50

51

52

35
56

57

58

36
59

60

61

37
62

63

67
70

71

[0101] The invention nucleic acid sequences Seq. ID No. 1 to Seq. ID No. 37 and 67 of the determined candidate genes and the determined amino acid sequences Seq. ID No. 39 to Seq. ID Nos. 63 and 68-71 are described in the following sequence protocol.

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[0194]

	Number	Date	Country
Parent	09647801	Dec 2000	US
Child	10330051	Dec 2002	US

Human nucleic acid sequences which are overexpressed in normal pancreas tissue

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