Genome-wide Scan Identifies a Novel Locus Associated with Aggressive Prostate Cancer. S. I. Berndt1, Z. Wang1,2, M. Yeager1,2, W. R. Diver3, S. Gapstur3, V. L. Stevens3, D. Albanes1, S. Weinstein1, J. Virtamo4, J. Cornu5, O. Cussenot5, G. Cancel-Tauset5, S. Lindstr÷m6, P. Kraft6, D. Hunter6, L. Amundadottir1, A. Black1, J. Sampson1, K. Jacobs1, M. Tucker1, S. J. Chanock1 1) Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD; 2) Core Genotyping Facility, Advanced Technology Program, SAIC Frederick, Inc., NCI-Frederick, Frederick, MD; 3) Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA; 4) Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finland; 5) CeRePP Hopital Tenon, Assistance Publique-H˘pitaux de Paris, Paris, France; 6) Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.

   Prostate cancer is the most common cancer in men, but the aggressiveness of the disease varies widely. Some prostate cancers are aggressive, leading to invasive or fatal disease. Others are indolent and unlikely to pose a serious health threat within a mans lifetime. Genome-wide association studies (GWAS) have identified over 70 loci associated with prostate cancer risk; however, none are specific for aggressive disease, which is critical for clinical risk prediction and prevention. We conducted a GWAS of 4,600 prostate cancer cases (including 4,545 cases with Gleason score) and 2,941 controls of European ancestry from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial using the Illumina Omni2.5 chip (stage 1). To identify genetic loci associated with prostate cancer aggressiveness, we conducted a case-only analysis using Gleason score, which is pathological measure of tumor aggressiveness, in a linear regression model. The most promising loci with P0.001 from this model were taken forward for replication in 6,572 cases (including 5,353 cases with Gleason score) and 6,391 controls of European ancestry from five studies using a custom Illumina iSelect chip (stage 2). A meta-analysis of stage 1 and stage 2 case-only results for Gleason score yielded one locus at 5q14.3, near RASA1/CCNH, that was associated with increased tumor aggressiveness at a genome-wide significance level (=0.11, P=6.90x10-11). Case-control analyses stratified by disease aggressiveness further demonstrated that the locus was specific for aggressive disease. The 5q14.3 SNP was associated with an increased risk of aggressive prostate cancer (n=1170 cases/9,332 controls, Gleason 8; OR=1.27, P=2.26x10-6), but not associated with non-aggressive disease (n=5421 cases/9332 controls, Gleason 6; OR=0.97, P=0.22). Additional replication is underway. The SNP is intronic within the RAS p21 protein activator 1 (RASA1) gene, which suppresses RAS signaling and angiogenesis, and is 79 kb downstream from cyclin H (CCNH), which is involved in transcription regulation and cell cycle control. Both genes have high biological relevance for prostate cancer, particularly for invasive disease. In conclusion, this is the first study to identify and replicate a locus that is specific for aggressive prostate cancer and not indolent prostate cancer, representing an important advance in the understanding the etiology of clinically significant aggressive prostate cancer.

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