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Gene Expression Profiling Identifies Clinically Relevant Subtypes of Prostate Cancer

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Gene Expression Profiling Identifies Clinically Relevant Subtypes of Prostate Cancer Gene expression profiling identifies clinically relevant subtypes of prostate cancer Jacques Lapointea,b,c, Chunde Lid, John P. Higginsa, Matt van de Rijna, Eric Baire, Kelli Montgomerya, Michelle Ferraric, Lars Egevadd, Walter Rayfordf, Ulf Bergerheimg, Peter Ekmand, Angelo M. DeMarzoh, Robert Tibshiranie,i, David Botsteinj, Patrick O. Brownb,k, James D. Brooksc,l, and Jonathan R. Pollacka,m Departments of aPathology, bBiochemistry, cUrology, eStatistics, iHealth Research and Policy, and jGenetics and kHoward Hughes Medical Institute, Stanford University, Stanford, CA 94305; dSection of Urology, Department of Surgical Science, Karolinska Institutet, SE-171 77 Stockholm, Sweden; fDepartment of Urology, Louisiana State University Health Sciences Center, New Orleans, LA 70112; gSection of Urology, Department of Biomedicine and Surgery, Linko¨ping University Hospital, 581 83 Linko¨ping, Sweden; and hDepartment of Pathology, Johns Hopkins University, Baltimore, MD 21205 Edited by Harold E. Varmus, Memorial Sloan–Kettering Cancer Center, New York, NY, and approved November 17, 2003 (received for review July 9, 2003) Prostate cancer, a leading cause of cancer death, displays a broad treatment, and which patients might be spared unnecessary and range of clinical behavior from relatively indolent to aggressive potentially harmful interventions. metastatic disease. To explore potential molecular variation un- The observed clinical heterogeneity of prostate cancer is likely derlying this clinical heterogeneity, we profiled gene expression in to reflect underlying molecular heterogeneity among tumors, 62 primary prostate tumors, as well as 41 normal prostate speci- which, although largely invisible under the light microscope, mens and nine lymph node metastases, using cDNA microarrays might be captured by profiling gene expression using DNA containing Ϸ26,000 genes. Unsupervised hierarchical clustering microarrays. Indeed, microarray profiling studies have identified readily distinguished tumors from normal samples, and further clinically relevant gene-expression subtypes in leukemia (6, 7), identified three subclasses of prostate tumors based on distinct lymphoma (8), breast cancer (9, 10), and lung cancer (11–13). patterns of gene expression. High-grade and advanced stage Although DNA microarray studies of prostate cancer have tumors, as well as tumors associated with recurrence, were dis- identified genes differentially expressed in tumor compared to proportionately represented among two of the three subtypes, nontumor samples (14–18) and genes whose expression cor- one of which also included most lymph node metastases. To relates with tumor grade, metastasis, and disease recurrence further characterize the clinical relevance of tumor subtypes, we (14, 17, 19, 20), to date, tumor subtypes based on gene expression evaluated as surrogate markers two genes differentially expressed have not been appreciated. among tumor subgroups by using immunohistochemistry on tissue Here we report a cDNA microarray-based study in prostate microarrays representing an independent set of 225 prostate cancer leading to the identification of biologically and clinically tumors. Positive staining for MUC1, a gene highly expressed in the relevant gene-expression tumor subtypes. Furthermore, we dem- subgroups with ‘‘aggressive’’ clinicopathological features, was onstrate that the protein expression levels for two genes, serving whereas as surrogate markers for tumor subtypes, are strong predictors ,(0.003 ؍ associated with an elevated risk of recurrence (P strong staining for AZGP1, a gene highly expressed in the other of tumor recurrence, independent of known risk factors. Our results support the existence of distinct gene expression subtypes ؍ subgroup, was associated with a decreased risk of recurrence (P 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were in prostate cancer, and their potential use in disease diagnosis and management. strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our re- Materials and Methods sults suggest that prostate tumors can be usefully classified ac- Gene Expression Profiling. Freshly frozen prostate surgical speci- cording to their gene expression patterns, and these tumor sub- mens were obtained from Stanford University, Karolinska In- types may provide a basis for improved prognostication and stitute, and Johns Hopkins University, with institutional review treatment stratification. board approval from the involved centers (see Supporting Note 1, which is published as supporting information on the PNAS orldwide, prostate cancer is the third most common web site). In total, we selected for study 62 primary prostate Wcancer and the cause of 6% of cancer deaths in men (1). tumors (61 adenocarcinomas and one adenoid cystic tumor), 41 Its incidence and mortality vary in different parts of the world matched normal prostate tissues (from the noncancerous region and are highest in Western countries (2). In the United States, of the prostate), and nine unmatched (i.e., different patient) it is the most frequently diagnosed and the second leading cause pelvic lymph node metastases. Detailed pathological and clinical of cancer death in men (3). Despite these high death rates, data for specimens are provided in Table 2, which is published MEDICAL SCIENCES prostate cancer is often an indolent disease, and patients can as supporting information on the PNAS web site. Gene expres- remain asymptomatic for years. The widespread use of serum sion profiling was performed essentially as described (9), by prostate-specific antigen (PSA) screening has led to identifica- using cDNA microarrays containing 26,260 different human tion of an increasing number of asymptomatic low-stage tumors genes (UniGene clusters). More detailed information, includ- in younger men (4, 5). An important clinical question has ing data selection and manipulation methods, is available in become whether and how aggressively to treat such patients with localized prostate cancer. Currently, prognostication and treatment stratification at the This paper was submitted directly (Track II) to the PNAS office. time of diagnosis are based on clinical stage, biopsy Gleason Abbreviations: PSA, prostate-specific antigen; FDR, false discovery rate. grade (a measure of tumor differentiation), and serum PSA lTo whom correspondence may be addressed at: Department of Urology, Stanford Univer- sity School of Medicine, S287, 300 Pasteur Drive, Stanford, CA 94305-5118. E-mail: levels. In cases treated by radical prostatectomy, prognosis can [email protected]. be refined by using pathological stage and grade. However, these mTo whom correspondence may be addressed at: Department of Pathology, Stanford prognostic indicators do not accurately predict clinical outcome University School of Medicine, CCSR 3245A, 269 Campus Drive, Stanford, CA 94305-5176. for individual patients. Improved markers are needed to deter- E-mail: [email protected]. mine which patients might benefit from a more aggressive © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0304146101 PNAS ͉ January 20, 2004 ͉ vol. 101 ͉ no. 3 ͉ 811–816 Downloaded by guest on October 1, 2021 Supporting Note 2, which is published as supporting information DCI, DECR2; Fig. 1i) and protein synthesis (e.g., RPL13, on the PNAS web site. RPS15, RPS9). Subtype I tumors were associated with two features of gene expression (Fig. 1 c and f), one of which (Fig. Tissue Microarrays. A tissue arrayer (Beecher Instruments, Sun 1f) included genes also expressed in normal prostate epithelium, Prarie, WI) was used to construct a prostate cancer tissue such as AZGP1 (24) and ARSDR1 (25). Subtype II represented microarray comprising an independent set of 225 formalin-fixed, the largest tumor subclass and, in addition to having a charac- paraffin-embedded primary prostate tumor cases selected from teristic gene expression feature (Fig. 1e), also shared expression diagnostic radical prostatectomy specimens collected at Stanford features with tumor subtype III (Fig. 1 j and l). University, with institutional review board approval. Duplicate 0.6-mm tumor cores represented each case, and the series was Tumor Subtypes Are Associated with Distinct Clinicopathological associated with a minimum clinical follow-up of 5 years and a Features. As noted above, primary tumors within subgroup III median follow-up of 8 years. Primary antibodies directed against shared an expression signature with unmatched lymph node MUC1 (SC-7313, Santa Cruz Biotechnology) and AZGP1 (SC- metastases. To gain further insight into the biological and clinical 11242, Santa Cruz Biotechnology) were used for immunohisto- relevance of new molecular subtypes, we examined the distri- chemical staining. More detailed information is available in bution of clinicopathological parameters among primary tumors Supporting Note 3, which is published as supporting information (Fig. 1b). High grade and advanced stage tumors were more on the PNAS web site. highly represented among tumor subgroups II and III (P ϭ 0.04, ␹2 test; Table 4, which is published as supporting information on Results the PNAS web site). Seven tumors associated with early recur- Identification of Prostate Tumor Subtypes. To survey the molecular rence in our dataset were also found to reside only within variation among prostate tumors, we profiled gene expression in subgroups II and III. Consistent with these observations,
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