Abstract LB-448: Genome-wide association study identifies new prostate cancer susceptibility loci
Authors: Schumacher Fredrick R. , Berndt Sonja I. , Siddiq Afshan , Jacobs Kevin , Wang Zhaoming , Lindstrom Sara , Stevens Victoria L. , Chen Constance , Mondul Alison M. , Travis Ruth C. , Stram Daniel O. , Eeles Rosalind A. , Easton Douglas F. , Giles Graham , Severi Gianluca , Gronberg Henrik , Wiklund Fredrik , Allen Naomi E. , Andriole Gerald L. , Barricarte Aurelio , Boeing Heiner , Bas Bueno de Mesquita H. , Crawford E. David , Diver W. Ryan , Gonzalez Carlos A. , Garziano J. Michael , Giovannucci Edward L. , Johansson Mattias , Marchand Loic Le , Ma Jing , Sier Sabina , Stattin Par , Stampfer Meir J. , Tjonneland Anne , Vineis Paolo , Virtamo Jarmo , Vogel Ulla , Weinstein Stephanie J. , Yeager Meredith , Thun Michael J. , Kolonel Laurence N. , Henderson Brian E. , Albanes Demetrius , Hayes Richard B. , Feigelson Heather Spencer , Riboli Elio , Hunter David J. , Chanock Stephen J. , Haiman Christopher A. , Kraft Peter 
Published: July 2012

Abstract
Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding etiology or factors influencing clinical outcome. Although PrCa genome-wide association studies (GWAS) have identified at least 30 distinct susceptibility loci for overall risk, the critical clinical question is determining who will develop advanced as opposed to indolent disease. To identify additional PrCa susceptibility loci, particularly for advanced PrCa, we conducted a GWAS of 2,782 prospectively ascertained advanced PrCa cases (Gleason grade 8+ or tumor stage C/D) and 4,458 matched controls of European ancestry from the NCI Breast & Prostate Cancer Cohort Consortium (BPC3). Case and control genotype frequencies were compared using a 1-df trend test within each cohort, and then combined using fixed effect meta-analysis for 571,243 single nucleotide polymorphisms (SNPs). In our Stage 1 GWAS, we found associations (P&lt;0.05) and consistent per-allele odds ratios (OR) with advanced PrCa for a majority of previously reported PrCa loci associated with overall risk. We did not observe associations with the proposed advanced-only region 17p12 or 22q13.1 after excluding overlapping subjects in the initial report (P=0.39). The advanced-only marker on chromosome 9q33.2 was nominally associated with advanced PrCa (rs1571801, P=1.4×10−3), but previous results in BPC3 (10,501 cases and 10,831 controls) found no evidence of difference between advanced and non-advanced PrCa (case-only test for heterogeneity P=0.50). No novel regions were detected at genome-wide significance in Stage 1 (P&lt;5×10−8). In Stage 2 we performed in silico replication for 4,679 of the most promising novel markers (P&lt;=0.02) identified in Stage 1 using data from two previous GWAS conducted in the UK and Australia (5,504 PrCa cases/5,834 controls) and the Cancer of the Prostate in Sweden Study (CAPS; 1,854 PrCa cases/898 controls). We identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884: OR=1.14, P=4.3 × 10−8) and confirmed a suggested locus at 12q13 (rs902774: OR=1.17, P=8.6×10−9). The estimated per-allele OR between advanced and non-advanced PrCa did not differ (case-only test for heterogeneity P&gt;0.60). Furthermore, we identified several genome-wide significant markers (P&lt;5×10−8) in known PrCa loci while conditioning on the index signal, suggesting multiple risk markers may exist. Although our Stage 1 GWAS was adequately powered (&gt;90%) to detect a marker with a per-allele OR of 1.18 and minor allele frequency of 40%, we identified no loci primarily associated with advanced PrCa. This suggests that-unlike unique breast cancer markers associated with estrogen-receptor positive and negative tumors-there are very few, if any, common markers with moderate effects differentially associated with advanced or non-advanced PrCa.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-448. doi:10.1158/1538-7445.AM2011-LB-448