Patent Grant
8871451
1. Technical Field
This document relates to methods and materials involved in identifying, assessing, and monitoring prostate cancer in male mammals.
2. Background Information
Cancer is a general term for diseases characterized by uncontrolled, abnormal growth of cells. The resulting mass, or tumor, can invade and destroy surrounding normal tissues. In addition, cancer cells from the tumor can spread through the blood or lymph to start new cancers in other parts of the body, or metastases.
Prostate cancer occurs when a malignant tumor forms in the tissue of the prostate. The prostate is a gland in the male reproductive system located below the bladder and in front of the rectum. The main function of the prostate gland, which is about the size of a walnut, is to make fluid for semen. Although there are several cell types in the prostate, nearly all prostate cancers start in the gland cells. This type of cancer is known as adenocarcinoma.
Prostate cancer is the second leading cause of cancer-related death in American men. Most of the time, prostate cancer grows slowly. Autopsy studies show that many older men who died of other diseases also had prostate cancer that neither they nor their doctor were aware of. Sometimes, however, prostate cancer can grow and spread quickly. It is important to be able to distinguish prostate cancers that will grow slowly from those that will grow quickly since treatment can be especially effective when the cancer has not spread beyond the region of the prostate. Finding ways to detect cancers early can improve survival rates.
This document provides methods and materials related to identifying, assessing, and monitoring prostate cancer in male mammals (e.g., humans). For example, this document provides arrays for detecting polypeptides or nucleic acids that can be used to identify prostate cancer in mammals. Such arrays can allow prostate cancer to be identified in mammals based on differences in the levels of many polypeptides or nucleic acids in biological samples from mammals that have prostate cancer as compared to the corresponding levels in biological samples from mammals that do not have prostate cancer.
Screening for prostate cancer has been widely performed by measuring serum levels of prostate-specific antigen (PSA). However, effective use of the PSA serum assay in general population screening is inhibited by a lack of sensitivity and specificity. Specific, sensitive, and non-invasive methods of screening mammals for cancer (e.g., prostate cancer) can allow cancer to be detected earlier. Early detection of cancer in mammals can allow the mammals to be treated sooner and improve their prognosis. Screening methods having adequate specificity with low false positive rates can reduce unnecessary treatment and suffering.
This document is based, in part, on the discovery of nucleic acid sequences that are predicted to encode extracellular or membrane-associated polypeptides, and that are differentially expressed in cancerous and non-cancerous prostate epithelial cells. This document also is based, in part, on the discovery of nucleic acid sequences that are predicted to encode polypeptides, and that are expressed in prostate cells at a high level relative to other cell types. The levels of transcripts and/or polypeptides encoded by these nucleic acids can be used to distinguish mammals with prostate cancer from mammals without prostate cancer. For example, a mammal that is found to have serum containing one or more than one polypeptide encoded by a nucleic acid listed in Table 2 at a level that is different (e.g., greater than or less than) than the average level observed in control serum can be classified as having prostate cancer. In some cases, a mammal that is found to have serum containing one or more than one polypeptide encoded by a nucleic acid listed in Table 2 and one or more than one polypeptide encoded by a nucleic acid listed in Table 3 at a level that is different (e.g., greater than or less than) than the average level observed in control serum can be classified as having prostate cancer. In some cases, a mammal that is found to have prostate cells expressing one or more than one polypeptide encoded by a nucleic acid listed in Table 4 at a level that is greater than the average level observed in control prostate cells can be classified as having prostate cancer. The levels of nucleic acids and/or polypeptides encoded by nucleic acids listed in Table 2 also can be used to evaluate cancer aggressiveness, monitor cancer progression, predict cancer outcome, and monitor response to treatment in mammals. In some cases, the level of one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2 and the level of one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 3 can be used to evaluate cancer aggressiveness, monitor cancer progression, predict cancer outcome, or monitor the response to cancer treatment in mammals.
In general, one aspect of this document features a method for identifying a mammal as having prostate cancer. The method comprising, or consists essentially of, (a) determining whether or not a mammal has a prostate cancer fluid profile, and (b) classifying the mammal as having prostate cancer if the mammal has the prostate cancer fluid profile and classifying the mammal as not having prostate cancer if the mammal does not have the prostate cancer fluid profile. The mammal can be a human. The method can comprise using blood, serum, plasma, urine, semen, or seminal fluid to assess the presence or absence of the prostate cancer fluid profile.
In another aspect, this document features a method for identifying a mammal as having prostate cancer. The method comprises, or consists essentially of, (a) determining whether or not a mammal has a prostate cancer cell profile, and (b) classifying the mammal as having prostate cancer if the mammal has the prostate cancer cell profile and classifying the mammal as not having prostate cancer if the mammal does not have the prostate cancer cell profile. The mammal can be a human. The method can comprise using prostate cells obtained from a needle biopsy to assess the presence or absence of the prostate cancer cell profile.
In another aspect, this document features a method for assessing the effectiveness of a treatment for prostate cancer. The method comprises, of consists essentially of, determining whether or not a mammal having prostate cancer and having received a treatment for the prostate cancer has a prostate cancer fluid profile to the same or greater degree than that observed prior to the treatment, wherein the presence of the prostate cancer fluid profile to the same or greater degree than that observed prior to the treatment indicates that the treatment is ineffective. The mammal can be a human. The method can comprise using blood, serum, plasma, urine, semen, or seminal fluid to assess the presence or absence of the prostate cancer fluid profile to the same or greater degree than that observed prior to the treatment.
In another aspect, this document features a method for assessing the effectiveness of a treatment for prostate cancer. The method comprises, or consists essentially of, determining whether or not a mammal having prostate cancer and having received a treatment for the prostate cancer has a prostate cancer cell profile to the same or greater degree than that observed prior to the treatment, wherein the presence of the prostate cancer cell profile to the same or greater degree than that observed prior to the treatment indicates that the treatment is ineffective. The mammal can be a human. The method can comprise using prostate cells obtained from a needle biopsy to assess the presence or absence of the prostate cancer cell profile to the same or greater degree than that observed prior to the treatment.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references (e.g., the records associated with GenBank accession or GI numbers) mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
This document provides methods and materials related to identifying, assessing, and monitoring prostate cancer in male mammals. For example, this document provides arrays for detecting nucleic acids or polypeptides that can be used to identify, assess, and/or monitor prostate cancer in male mammals. Such arrays can allow prostate cancer to be identified, assessed, and/or monitored based on the levels of nucleic acids or polypeptides in a biological sample from a mammal.
As described herein, this document provides methods and materials for identifying prostate cancer in male mammals (e.g., humans). In some embodiments, a mammal can be classified as having prostate cancer if it is determined that a biological fluid (e.g., blood, urine, seminal fluid, or serum) from the mammal contains one or more than one polypeptide (e.g., two, three, four, five, six, seven, eight, nine, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or more than 60 polypeptides), or a fragment thereof, encoded by a nucleic acid listed in Table 2 (e.g., a category 1, 2, or 3 nucleic acid listed in Table 2) at a level that is greater than the average level of the same one or more than one polypeptide observed in corresponding control fluid from control mammals. In some cases, a mammal can be classified as having prostate cancer if it is determined that a biological fluid (e.g., blood, urine, seminal fluid, or serum) from the mammal contains one or more than one polypeptide, or fragment thereof, encoded by a nucleic acid listed in Table 2, and one or more than one polypeptide, or fragment thereof, encoded by a nucleic acid listed in Table 3 at a level that is greater than the average level of the same one or more than one polypeptide observed in corresponding control fluid from control mammals. In some cases, a mammal can be classified as having prostate cancer if it is determined that prostate cells from the mammal contain one or more than one nucleic acid or polypeptide, or fragment thereof, encoded by a nucleic acid listed in Table 4 (e.g., a category 1, 2, or 3 nucleic acid listed in Table 4) at a level that is greater than the average level (e.g., via a subset analysis) of the same one or more than one nucleic acid or polypeptide in corresponding control (e.g., non-cancerous) prostate cells.
In some cases, a mammal can be classified as having prostate cancer if it is determined that a biological fluid (e.g., blood, urine, seminal fluid, or semen) from the mammal has a prostate cancer fluid profile. For the purpose of this document, the term “prostate cancer fluid profile” as used herein refers to a polypeptide profile in a biological fluid (e.g., blood, plasma, serum, urine, semen, or seminal fluid) where 16 or more (e.g., 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, or more) polypeptides, or fragments thereof, encoded by nucleic acids listed in Table 2 are present at a level greater than the level observed in a corresponding control biological fluid from a control mammal. In some cases, the prostate cancer fluid profile can be a polypeptide profile in a biological fluid where 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percent of the polypeptides, or fragments thereof, encoded by nucleic acids listed in Table 2 are present at a level greater than the level observed in corresponding control biological fluid from a control mammal.
In some cases, a mammal can be classified as having prostate cancer if it is determined that prostate cells from the mammal have a prostate cancer cell profile. The term “prostate cancer cell profile” as used herein refers to a profile where prostate cells express 12 or more (e.g., 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or more) nucleic acids or polypeptides, or fragments thereof, encoded by nucleic acids listed in Table 4 at a level greater than the level observed in corresponding control prostate cells. In some cases, the prostate cancer cell profile can be a profile in prostate cells where 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percent of the nucleic acids or polypeptides, or fragments thereof, encoded by nucleic acids listed in Table 4 are present at a level greater than the level observed in corresponding control prostate cells.
Prostate cancer can be identified in any male mammal such as a male human, dog, horse, mouse, or rat. The mammal can be middle-aged or older. For example, a male human can be 35 years old or older (e.g., 40, 45, 50, 55, 60, 65, 70, 75 years old or older).
Any biological fluid can be evaluated to determine if it contains one or more than one polypeptide or nucleic acid, or fragment thereof, encoded by a nucleic acid listed in Table 2 at a level that is greater than the average level observed in a corresponding control biological fluid. For example, blood (e.g., peripheral blood or venous prostate blood), plasma, serum, urine, semen, and/or seminal fluid can be evaluated to determine if the fluid contains one or more than one polypeptide or nucleic acid encoded by a nucleic acid listed in Table 2 at a level that is greater than the average level observed in a corresponding control biological fluid. In some cases, a biological fluid (e.g., blood, plasma, serum, urine, semen, and/or seminal fluid) can be evaluated to determine if the fluid contains one or more than one polypeptide or nucleic acid, or fragment thereof, encoded by a nucleic acid listed in Table 2, and one or more than one polypeptide or nucleic acid, or fragment thereof, encoded by a nucleic acid listed in Table 3 at a level that is greater than the average level observed in a corresponding control biological fluid. In some cases, a biological fluid can be evaluated to determine if the fluid has a prostate cancer fluid profile.
Any type of biological sample can be evaluated to determine if it contains one or more than one nucleic acid or polypeptide, or fragment thereof, encoded by a nucleic acid listed in Table 4 at a level that is greater than the average level observed in a corresponding control biological sample. For example, biological fluids can be evaluated including, without limitation, blood, plasma, serum, urine, semen, and seminal fluid. In some cases, prostate cells can be evaluated including, without limitation, prostate cells in prostate tissue and metastatic prostate cancer cells in blood, urine, cellular fragments, or in tissues other than prostate tissue such as lung tissue and lymph node tissue. In some cases, prostate cells can be evaluated to determine whether or not the cells have a prostate cancer cell profile.
Any method can be used to obtain a biological sample from a mammal. For example, a blood sample can be obtained by peripheral venipuncture, and urine samples can be obtained using standard urine collection techniques. In some cases, a tissue sample can be obtained from a tissue biopsy (e.g., a needle biopsy), from a transurethral resection of the prostate (TURP), or from a radical prostatectomy. A sample can be manipulated prior to being evaluated for the level of one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2 or 3. A sample also can be manipulated prior to being evaluated for a prostate cancer fluid profile or a prostate cancer cell profile. For example, a prostate biopsy specimen can be frozen, embedded, and/or sectioned prior to being evaluated. In addition, nucleic acids and/or polypeptides can be extracted from a sample, purified, and evaluated to determine the level of one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2 or 3. In some cases, nucleic acids and/or polypeptides extracted from a sample can be evaluated for a prostate cancer cell profile or a prostate cancer fluid profile. In some cases, a tissue sample can be disrupted to obtain a cell lysate. Once obtained, the cell lysate can be analyzed for the level of one or more than one polypeptide encoded by a nucleic acid listed in Table 4. A cell lysate also can be evaluated for a prostate cancer cell profile. In some cases, prostate cells can be isolated from other cells or tissues prior to analysis. For example, prostate cells can be isolated from tissues using laser capture microdissection prior to being evaluated for the level of one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 4. In some cases, prostate cells can be evaluated for a prostate cancer cell profile.
The level of any number of nucleic acids or polypeptides encoded by nucleic acids listed in Table 2 can be evaluated to identify prostate cancer. For example, the level of one or more than one (e.g., two, three, four, five, six, seven, eight, nine, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or more than 60) nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2 can be used to identify prostate cancer. In some cases, the level of one or more than one (e.g., two, three, four, five, six, seven, eight, nine, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or more than 60) nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2, and the level of one or more than one (e.g., two, three, four, five, six, or more than 6) nucleic acid or polypeptide encoded by a nucleic acid listed in Table 3 can be used to identify prostate cancer. In some cases, the level of one or more than one (e.g., two, three, four, five, six, seven, eight, nine, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50) nucleic acid or polypeptide encoded by a nucleic acid listed in Table 4 can be used to identify prostate cancer.
The level of a nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2 or 3 in a biological sample can be greater than or less than the average level observed in corresponding control samples. Typically, a nucleic acid or polypeptide can be classified as being present at a level that is greater than or less than the average level observed in control samples if the levels differ by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or more percent. In some cases, a nucleic acid or polypeptide can be classified as being present at a level that is greater than or less than the average level observed in control samples if the levels differ by greater than 1-fold (e.g., 1.5-fold, 2-fold, 3-fold, or more than 3-fold). Control samples typically are obtained from one or more mammals of the same species as the mammal being evaluated. When identifying prostate cancer, control samples (e.g., control serum or urine samples) can be obtained from healthy mammals, such as male humans who do not have prostate cancer. In some cases, control samples can be non-cancerous prostate cells or tissues from male mammals having prostate cancer (e.g., non-neoplastic cells adjacent to prostate cancer cells). Control samples can be obtained from any number of mammals. For example, control samples can be obtained from one or more mammals (e.g., 10, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 1000, or more than 1000 mammals) from the same species as the mammal being evaluated.
Any method can be used to determine whether or not a polypeptide is present in a biological sample at a level that is greater than or less than the average level observed in corresponding control samples. For example, the level of a particular polypeptide can be measured using, without limitation, immuno-based assays (e.g., ELISA and immunohistochemistry), Western blotting, arrays for detecting polypeptides, two-dimensional gel analysis, chromatographic separation, mass spectrometry (MS), tandem mass spectrometry (MS/MS), or liquid chromatography (LC)-MS. Methods of using arrays for detecting polypeptides include, without limitation, those described herein. Such methods can be used to determine simultaneously the relative levels of multiple polypeptides.
Any method can be used to determine whether or not a specific nucleic acid is present in a biological samples at a level that is greater than or less than the average level observed in corresponding control samples. For example, the level of a particular nucleic acid can be measured using, without limitation, Northern blotting, slot blotting, quantitative PCR, RT-PCR, or chip hybridization techniques. Methods for chip hybridization assays include, without limitation, those described herein. Such methods can be used to determine simultaneously the relative expression levels of multiple nucleic acids.
Methods provided herein for identifying prostate cancer in male mammals can be used in combination with one or more methods typically used to identify prostate cancer. Such methods include, without limitation, digital rectal exam, transrectal ultrasonography, intravenous pyelogram, cystoscopy, and blood and urine tests for levels of prostatic acid phosphatase (PAP) and PSA. A mammal can be evaluated regularly for prostate cancer. For example, a mammal can be evaluated once a year for as long as the mammal is alive. In some cases, male humans can be evaluated for prostate cancer once every year beginning at age 35. Mammals that are susceptible to develop prostate cancer can be screened more frequently, and screening can be started at an earlier age. For example, mammals having a genetic predisposition to develop cancer, a family history of cancer, or a trend towards an increased serum level of one or more polypeptides encoded by a nucleic acid listed in Table 2 can be assessed more frequently.
This document also provides materials and methods for assessing prostate cancer in a mammal. For example, this document provides materials and methods for assessing the aggressiveness of prostate cancer in a mammal. Methods typically used to assess the aggressiveness of prostate cancer in a mammal include determining the Gleason score, the serum PSA level, and whether or not the serum PSA level increases over time and rate of PSA increases (PSA velocity). The Gleason score is a measure of how different cancer cells are from normal cells. The more different the cancer cells are from non-cancer cells, the more likely that the cancer will spread quickly. In some cases, the aggressiveness of prostate cancer can be assessed based on the numbers and/or levels of nucleic acids or polypeptides encoded by nucleic acids listed in Table 2 in a biological fluid from a mammal. The greater the number of different nucleic acids or polypeptides encoded by nucleic acids listed in Table 2 in a biological fluid from the mammal, the more aggressive the prostate cancer in the mammal. In addition, the greater the differences between the levels of the nucleic acids or polypeptides encoded by nucleic acids listed in Table 2 in a biological fluid from a mammal and the average levels of the same nucleic acids or polypeptides in control samples, the more likely the prostate cancer will move rapidly and progress in the mammal. In some embodiments, the aggressiveness of prostate cancer can be assessed based on the levels of nucleic acids or polypeptides encoded by nucleic acids listed in Table 2, and the level of one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 3 in a biological fluid from a mammal. In some cases, the levels of nucleic acids or polypeptides encoded by nucleic acids listed in Table 2 in a biological fluid can be used in combination with one or more other factors to determine whether or not a mammal having prostate cancer is susceptible to a poor outcome. For example, levels of nucleic acids or polypeptides encoded by nucleic acids listed in Table 2 in a biological fluid from a mammal having prostate cancer can be used in combination with the clinical stage, the serum PSA level, and/or the Gleason pattern of the prostate cancer to determine whether or not the mammal is likely to have to a poor outcome. In some cases, the aggressiveness of prostate cancer can be assessed based on the numbers and/or levels of nucleic acids or polypeptides encoded by nucleic acids listed in Table 4 in a biological sample from a mammal.
Information about the aggressiveness of prostate cancer can be used to guide treatment selection. For example, a mammal identified as having more aggressive prostate cancer can be treated earlier and more aggressively than a mammal identified as having less aggressive prostate cancer. A more aggressive treatment can include radical prostatectomy. A mammal identified as having less aggressive prostate cancer may undergo “watchful waiting” while having little or no standard treatment, particularly if the mammal is elderly.
Once prostate cancer has been identified in a mammal (e.g., a human), the mammal can be subsequently evaluated or monitored over time for progression of the cancer, particularly if the cancer was identified as being aggressive. For example, prostate cancer in a mammal can be assessed as having progressed if it is determined that a biological fluid from the mammal (e.g., serum or urine from the mammal) contains one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2 at a level that is greater than the level of the same one or more than one nucleic acid or polypeptide observed in a corresponding biological fluid (e.g., serum or urine) obtained previously from the same mammal. In some cases, prostate cancer in a mammal can be assessed as having progressed if it is determined that a biological fluid from the mammal (e.g., serum or urine from the mammal) contains one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2, and one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 3 at a level that is greater than the level of the same one or more nucleic acids or polypeptides observed in a corresponding biological fluid (e.g., serum or urine) obtained previously from the same mammal. In some cases, prostate cancer in a mammal can be assessed as having progressed if it is determined that a biological fluid from the mammal has a prostate cancer fluid profile to a level greater than that observed in a corresponding biological fluid obtained previously from the same mammal. In some cases, prostate cancer in a mammal can be assessed as having progressed if it is determined that a sample (e.g., a sample of prostate cells) from the mammal contains one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 4 at a level that is greater than the level of the same one or more than nucleic acid or polypeptide observed in a corresponding sample obtained previously from the same mammal. In some cases, prostate cancer in a mammal can be assessed as having progressed if it is determined that a sample (e.g., a sample of prostate cells) from the mammal has a prostate cancer cell profile to a level greater than that observed in a corresponding sample obtained previously from the same mammal. A mammal can be monitored for progression of prostate cancer over any period of time with any frequency. For example, a male mammal can be monitored once a year, twice a year, three times a year, or more frequently. In some cases, a mammal can be monitored every three months for five years or once a year for as long as the mammal is alive.
A mammal can also be assessed for progression of prostate cancer before, during, and after treatment for prostate cancer. For example, a mammal can be assessed for progression (e.g., metastasis) of prostate cancer while being treated with androgen deprivation therapy or following radical prostatectomy. Assessing a mammal for progression of prostate cancer during treatment of the mammal for prostate cancer can allow the effectiveness of the prostate cancer therapy to be determined. For example, a decrease in the level of one or more than one nucleic acid or polypeptide encoded by a nucleic acid listed in Table 2 in a biological fluid (e.g., serum or urine) from a mammal being treated for prostate cancer as compared to the level of the same one or more nucleic acids or polypeptides observed in a corresponding biological fluid (e.g., serum or urine) obtained previously from the same mammal can indicate that the therapy is effective. In some cases, a therapy can be assessed as being effective if it is determined that a fluid from a mammal having prostate cancer and having received a prostate cancer treatment has a prostate cancer fluid profile to a level less than that observed in corresponding fluid from the same mammal prior to the treatment.
This document also provides methods and materials to assist medical or research professionals in determining whether or not a mammal has prostate cancer. Medical professionals can be, for example, doctors, nurses, medical laboratory technologists, and pharmacists. Research professionals can be, for example, principle investigators, research technicians, postdoctoral trainees, and graduate students. A professional can be assisted by (1) determining the level of one or more than one polypeptide or nucleic acid encoded by a nucleic acid listed in Table 2 in a sample, and (2) communicating information about that level to that professional.
Any method can be used to communicate information to another person (e.g., a professional). For example, information can be given directly or indirectly to a professional. In addition, any type of communication can be used to communicate the information. For example, mail, e-mail, telephone, and face-to-face interactions can be used. The information also can be communicated to a professional by making that information electronically available to the professional. For example, the information can be communicated to a professional by placing the information on a computer database such that the professional can access the information. In addition, the information can be communicated to a hospital, clinic, or research facility serving as an agent for the professional.
This document also provides arrays for detecting polypeptides. The arrays provided herein can be two-dimensional arrays, and can contain at least two different polypeptides capable of detecting polypeptides, such as antibodies (e.g., at least three, at least five, at least ten, at least 20, at least 30, at least 40, at least 50, or at least 60 different polypeptides capable of detecting polypeptides). The arrays provided herein also can contain multiple copies of each of many different polypeptides. In addition, the arrays for detecting polypeptides provided herein can contain polypeptides attached to any suitable surface (e.g., plastic or glass).
A polypeptide capable of detecting a polypeptide can be naturally occurring, recombinant, or synthetic. The polypeptides immobilized on an array also can be antibodies. An antibody can be, without limitation, a polyclonal, monoclonal, human, humanized, chimeric, or single-chain antibody, or an antibody fragment having binding activity, such as a Fab fragment, F(ab′) fragment, Fd fragment, fragment produced by a Fab expression library, fragment comprising a VL or VH domain, or epitope binding fragment of any of the above. An antibody can be of any type, (e.g., IgG, IgM, IgD, IgA or IgY), class (e.g., IgG1, IgG4, or IgA2), or subclass. In addition, an antibody can be from any animal including birds and mammals. For example, an antibody can be a mouse, chicken, human, rabbit, sheep, or goat antibody. Such an antibody can be capable of binding specifically to a polypeptide encoded by a nucleic acid listed in Table 2 or 3. The polypeptides immobilized on the array can be members of a family such as a receptor family, protease family, or an enzyme family.
Antibodies can be generated and purified using any suitable methods known in the art. For example, monoclonal antibodies can be prepared using hybridoma, recombinant, or phage display technology, or a combination of such techniques. In some cases, antibody fragments can be produced synthetically or recombinantly from a nucleic acid encoding the partial antibody sequence. In some cases, an antibody fragment can be enzymatically or chemically produced by fragmentation of an intact antibody. In addition, numerous antibodies are available commercially (Table 1). An antibody directed against a polypeptide encoded by a nucleic acid listed in Table 2 or 3 can bind the polypeptide at an affinity of at least 104 mol−1 (e.g., at least 105, 106, 107, 108, 109, 1010, 1011, or 1012 mol−1).
Any method can be used to make an array for detecting polypeptides. For example, methods disclosed in U.S. Pat. No. 6,630,358 can be used to make arrays for detecting polypeptides. Arrays for detecting polypeptides can also be obtained commercially, such as from Panomics, Redwood City, Calif.
This document also provides nucleic acid arrays. The arrays provided herein can be two-dimensional arrays, and can contain at least two different nucleic acid molecules (e.g., at least three, at least five, at least ten, at least 20, at least 30, at least 40, at least 50, or at least 60 different nucleic acid molecules). Each nucleic acid molecule can have any length. For example, each nucleic acid molecule can be between 10 and 250 nucleotides (e.g., between 12 and 200, 14 and 175, 15 and 150, 16 and 125, 18 and 100, 20 and 75, or and 50 nucleotides) in length. In some cases, an array can contain one or more cDNA molecules encoding, for example, partial or entire polypeptides. In addition, each nucleic acid molecule can have any sequence. For example, the nucleic acid molecules of the arrays provided herein can contain sequences that are present within the nucleic acids listed in Tables 2 and 3.
Typically, at least 25% (e.g., at least 30%, at least 40%, at least 50%, at least 60%, at least 75%, at least 80%, at least 90%, at least 95%, or 100%) of the nucleic acid molecules of an array provided herein contain a sequence that is (1) at least 10 nucleotides (e.g., at least 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or more nucleotides) in length and (2) at least about 95 percent (e.g., at least about 96, 97, 98, 99, or 100) percent identical, over that length, to a sequence present within a nucleic acid listed in Table 2 or 3. For example, an array can contain 60 nucleic acid molecules located in known positions, where each of the 60 nucleic acid molecules is 100 nucleotides in length while containing a sequence that is (1) 30 nucleotides is length, and (2) 100 percent identical, over that 30 nucleotide length, to a sequence of one of the nucleic acids listed in Table 2. Thus, a nucleic acid molecule of an array provided herein can contain a sequence present within a nucleic acid listed in Table 2 or 3 where that sequence contains one or more (e.g., one, two, three, four, or more) mismatches.
The nucleic acid arrays provided herein can contain nucleic acid molecules attached to any suitable surface (e.g., plastic or glass). In addition, any method can be use to make a nucleic acid array. For example, spotting techniques and in situ synthesis techniques can be used to make nucleic acid arrays. Further, the methods disclosed in U.S. Pat. Nos. 5,744,305 and 5,143,854 can be used to make nucleic acid arrays.
In some cases, a sample from a mammal can be assessed for auto-antibodies against a polypeptide encoded by any of the nucleic acid molecules provided herein. The presence of such auto-antibodies can indicate that the mammal has prostate cancer. For example, a blood sample from a human can be assessed for the presence of auto-antibodies to a polypeptide encoded by any of the nucleic acid molecules provided herein with the presence of such an auto-antibody indicating that that human has prostate cancer.
The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
Gene expression was profiled in prostate epithelial cells. Benign and malignant cells were laser capture microdissected from 100 prostate tissues and metastatic prostatic adenocarcinomas. Non-neoplastic prostate epithelial cells were collected from the tissues of 29 patients having prostate cancer. High-grade prostatic intraepithelial neoplasia (PIN) cells, metastatic prostate cancer cells, and primary Gleason pattern 3, 4, and 5 cells were collected from the remaining tissues. RNA was extracted from homogenous populations of captured cells and purified. Samples of total RNA were linearly amplified, labeled, and hybridized to U133 Plus 2.0 arrays (Affymetrix, Santa Clara, Calif.). The arrays were washed, stained, and scanned in accordance with Affymetrix protocols.
Secreted and membrane bound polypeptides associated with the Affymetrix probe sets were identified using two methods. First, RefSeq polypeptide sequence identifiers annotated to the probe set identifiers were abstracted from the Affymetrix U133 Plus 2.0 annotation file. These sequences were downloaded from NCBI and processed through a prediction pipeline, which included SignalP analysis, TargetP analysis, TMHMM analysis, and Phobius analysis. Polypeptides predicted to be secretory polypeptides by the SignalP and TargetP programs were further analyzed using the TMHMM and Phobius programs. Polypeptides that were not predicted to be secretory polypeptides by the SignalP program or the TargetP program were classified as non-secretory polypeptides. Secretory polypeptides predicted to have no transmembrane domains by the TMHMM program were classified as extracellular. Secretory polypeptides predicted to have two or more transmembrane domains were classified as membrane-associated polypeptides. Secretory polypeptides predicted to have only one transmembrane domain were analyzed using the Phobius program. Phobius predictions were used to differentiate polypeptides with N-terminal signal anchors (uncleaved) from polypeptides with N-terminal signal sequences (cleaved). The second method used to identify secreted and membrane polypeptides involved mining the localization annotated database of SWISS-PROT polypeptides. The SwissProt records for all human polypeptides were downloaded. All localization annotations were manually reviewed and categorized as extracellular (S), plasma membrane (M), or intracellular (I). All probe sets with annotated SwissProt polypeptides having cellular localization annotations were classified extracellular (S), plasma membrane (M), or intracellular (I). Localization classifications assigned by SwissProt annotations were given preference over classifications made by the prediction analyses. A set of 70 nucleic acids encoding extracellular and membrane-associated polypeptides was identified, including 53 nucleic acids that were annotated or predicted to encode extracellular polypeptides, and 17 nucleic acids that were annotated or predicted to encode membrane-associated polypeptides.
The value of the selected nucleic acids for use in identifying cancer was assessed using two methods. Fifty-four polypeptides, including all of the membrane-associated polypeptides, were selected based on up-regulation of corresponding RNA transcripts observed in prostate cancer cells as compared to non-neoplastic prostate cells. The initial list of differentially expressed nucleic acids was identified using several microarray analysis parameters, including:
a. PM/MM normalization and no transformation
b. PM only normalization and no transformation
c. PM/MM normalization and log 2 transformation
d. PM only normalization and log 2 transformation Expression values generated from these analysis methods were then used to make the following comparisons:
a. Gleason pattern 3 versus
b. Gleason pattern 3 versus
c. Gleason pattern 3+Gleason pattern 4 versus
d. Gleason pattern 3+Gleason pattern 4 versus
e. All Cancer versus
f. All Cancer versus
Nucleic acids demonstrating at least two fold up-regulation in cancer cells compared to non-neoplastic cells were cross-referenced with nucleic acids classified as encoding either secretory or membrane-associated polypeptides. The resulting list of nucleic acids was manually curated to remove cases with expression levels below the noise level of the microarray experiment, and cases having an expression profile that was over-biased by one or two aberrant cases.
The remaining sixteen nucleic acids were selected because they had a high level of expression in prostate cells and a prostate-preferential expression profile, without clear differential expression between cancer and non-cancer cells. Tissue specificity was quantitated by mining Expressed Sequence Tag transcripts.
The 70 nucleic acids selected were cross-referenced with the Cancer Genome Anatomy Project's SAGE Genie, the Ludwig Institute for Cancer Research MPSS database, the Human Protein Atlas database, and an EST tissue specificity analysis database. Based on these additional transcriptomic and immunohistochemistry annotations, the nucleic acids were prioritized with numeric rankings from 1 (highest priority) to three (lowest priority). The selected nucleic acids are listed in Tables 2-4.
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
This application is a continuation of U.S. patent application Ser. No. 12/442,685, filed on Mar. 24, 2009, which is a National Stage application under 35 U.S.C. §371 of International Application No. PCT/US2007/079423, having an International Filing Date of Sep. 25, 2007, which claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 60/847,057, filed on Sep. 25, 2006. The disclosures of these applications are incorporated herein by reference in their entirety.
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| Number | Date | Country | |
|---|---|---|---|
| 20130004974 A1 | Jan 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60847057 | Sep 2006 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12442685 | US | |
| Child | 13607296 | US |
