Gene expression profiling identifies clinically relevant subtypes of prostate cancer.

Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing approximately 26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with "aggressive" clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

[1]  Z. Hall.  Cancer , 1906, The Hospital.

[2]  A. Badenoch.  Urology , 1934, Glasgow Medical Journal.

[3]  A. Chadli.  THE CANCER CELL , 1924, La Presse medicale.

[4]  I. Forgacs.  GASTROENTEROLOGY , 1988, The Lancet.

[5]  D. Grignon,et al.  Basal cell hyperplasia, adenoid basal cell tumor, and adenoid cystic carcinoma of the prostate gland: an immunohistochemical study. , 1988, Human pathology.

[6]  R. Tremblay,et al.  Expression of Zn-alpha 2-glycoprotein and PSP-94 in prostatic adenocarcinoma. An immunohistochemical study of 88 cases. , 1990, The American journal of pathology.

[7]  M. Niwa,et al.  Immunohistochemical localization of Zn-alpha 2-glycoprotein in normal human tissues. , 1991, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[8]  D. Ota,et al.  MUC1 mucin expression as a marker of progression and metastasis of human colorectal carcinoma. , 1994, Gastroenterology.

[9]  A. Sonnenberg,et al.  Episialin (MUC1) overexpression inhibits integrin-mediated cell adhesion to extracellular matrix components , 1995, The Journal of cell biology.

[10]  Walsh,et al.  Prognostic significance of MUC1 epithelial mucin expression in breast cancer. , 1995, Human pathology.

[11]  J. Wesseling,et al.  A mechanism for inhibition of E-cadherin-mediated cell-cell adhesion by the membrane-associated mucin episialin/MUC1. , 1996, Molecular biology of the cell.

[12]  A. Harris,et al.  MUC1 (episialin) expression in non-small cell lung cancer is independent of EGFR and c-erbB-2 expression and correlates with poor survival in node positive patients. , 1998, Journal of clinical pathology.

[13]  K. Cummings,et al.  National trends in the epidemiology of prostate cancer, 1973 to 1994: evidence for the effectiveness of prostate-specific antigen screening. , 1998, Urology.

[14]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[15]  Levine,et al.  MUC1 Expression in Prostate Carcinoma: Correlation with Grade and Stage. , 1999, Molecular urology.

[16]  S. Takao,et al.  Mucin core protein expression in extrahepatic bile duct carcinoma is associated with metastases to the liver and poor prognosis , 1999, Cancer.

[17]  K. Gatter,et al.  Coexpression of MUC1 glycoprotein with multiple angiogenic factors in non-small cell lung cancer suggests coactivation of angiogenic and migration pathways. , 2000, Clinical Cancer Research.

[18]  S. Devesa,et al.  International trends and patterns of prostate cancer incidence and mortality , 2000, International journal of cancer.

[19]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[20]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[21]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Jeffrey A. Magee,et al.  Expression profiling reveals hepsin overexpression in prostate cancer. , 2001, Cancer research.

[23]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Welsh,et al.  Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. , 2001, Cancer research.

[25]  Roger E Bumgarner,et al.  Prostate short-chain dehydrogenase reductase 1 (PSDR1): a new member of the short-chain steroid dehydrogenase/reductase family highly expressed in normal and neoplastic prostate epithelium. , 2001, Cancer research.

[26]  A. Giatromanolaki,et al.  Tumor angiogenesis is associated with MUC1 overexpression and loss of prostate-specific antigen expression in prostate cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  K. Kinzler,et al.  Cell surface tumor endothelial markers are conserved in mice and humans. , 2001, Cancer research.

[28]  F. Bray,et al.  Cancer burden in the year 2000. The global picture. , 2001, European journal of cancer.

[29]  P. Altevogt,et al.  Tumor Cell Invasion Is Promoted by Activation of Protease Activated Receptor-1 in Cooperation with the αvβ5 Integrin* , 2001, The Journal of Biological Chemistry.

[30]  D. Botstein,et al.  Diversity of gene expression in adenocarcinoma of the lung , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  A W Partin,et al.  Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. , 2001, The Journal of urology.

[32]  S. Dhanasekaran,et al.  Delineation of prognostic biomarkers in prostate cancer , 2001, Nature.

[33]  E. Lander,et al.  Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  M. Bittner,et al.  Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling. , 2001, Cancer research.

[35]  W. Demark-Wahnefried,et al.  Zinc α-2-Glycoprotein Is Expressed by Malignant Prostatic Epithelium and May Serve as a Potential Serum Marker for Prostate Cancer , 2001 .

[36]  David E. Misek,et al.  Gene-expression profiles predict survival of patients with lung adenocarcinoma , 2002, Nature Medicine.

[37]  E. Latulippe,et al.  Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. , 2002, Cancer research.

[38]  Debashis Ghosh,et al.  alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer. , 2002, JAMA.

[39]  M. Hendrix,et al.  A molecular role for lysyl oxidase in breast cancer invasion. , 2002, Cancer research.

[40]  Masato Nakamura,et al.  Neuropilin 1 and neuropilin 2 co‐expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma , 2002, Cancer.

[41]  J. Trent,et al.  α-methylacyl-CoA racemase: A new molecular marker for prostate cancer , 2002 .

[42]  E. Lander,et al.  Gene expression correlates of clinical prostate cancer behavior. , 2002, Cancer cell.

[43]  J. Downing,et al.  Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. , 2002, Cancer cell.

[44]  Alicia Samuels,et al.  Cancer Statistics, 2003 , 2003, CA: a cancer journal for clinicians.

[45]  E. Lander,et al.  A molecular signature of metastasis in primary solid tumors , 2003, Nature Genetics.

[46]  P. Sismondi,et al.  Angiopoietin‐2 expression in breast cancer correlates with lymph node invasion and short survival , 2003, International journal of cancer.