Abstract 3863: Fine mapping and comprehensive resequencing analysis of a region of chromosome 11q13 reveals multiple independent loci associated with prostate cancer
Authors: Charles C. Chung, Julia Ciampa, Meredith Yeager, Kevin B. Jacobs, Richard B. Hayes, Zuoming Deng, Jesus Gonzalez-Bosquet, Peter Kraft, Berndt I. Sonja, Wacholder Sholom, Nick Orr, Kai Yu, Amy Hutchinson, Heather Spencer Feigelson, Michael J. Thun, W. Ryan Diver, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Fredrick R. Schumacher, Geraldine Cancel-Tassin, Olivier Cussenot, Antoine Valeri, Gerald L. Andriole, E. David Crawford, Christopher A. Haiman, Brian E. Henderson, Laurence Kolonel, Loic Le Marchand, Afshan Siddiq, Elio Riboli, Tim J. Key, Rudolf Kaaks, William B. Isaacs, Sarah D. Isaacs, Henrik Grönberg, Fredrik Wiklund, Jianfeng Xu, Lars J. Vatten, Kristian Hveem, Merethe Kumle, Margaret Tucker, Robert N. Hoover, Joseph F. Fraumeni, David J. Hunter, Gilles Thomas, Nilanjan Chatterjee, Stephen J. Chanock
Journal: Cancer Research (2010)

Abstract Two genome-wide association studies of prostate cancer identified single nucleotide polymorphism (SNP) markers in a region of chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative the region flanking the most significant marker, rs10896449, was fine mapped using common single nucleotide polymorphisms (SNPs) selected from a two-staged tagging strategy. Of the 120 SNPs analyzed in 10,272 cases and 9,123 controls of European origin, single locus analysis identified 18 SNPs below genome-wide significance (P &amp;lt; 10−8); rs10896449, initially reported remained most significant (P = 7.94 × 10−19). Multi-locus models that included the 18 significant SNPs sequentially identified a second association at rs12793759 (OR = 1.14 P = 4.76 × 10−5), independent of rs10896449 that remained significant after adjustment for multiple testing within the region. A third signal, rs10896438 (OR = 1.07, P = 5.92 × 10−3), independent of both rs10896449 and rs12793759 was detected. To comprehensively catalog genetic variants in strong LD with the above SNPs as well as to determine the region's LD pattern, next-generation sequence analysis of 123 kb (chr11: 68,642,755 - 68,765,690) was performed in 75 individuals of European origin. 447 SNPs with minor allele frequency (MAF) &amp;gt; 1% were identified, which included 180 novel SNPs. Based on r2 &amp;gt; 0.8, 105 SNPs are needed to monitor SNPs with MAF &amp;gt; 1%, whereas 62 SNPs are required for MAF &amp;gt; 5%. 51 SNPs with MAF &amp;gt; 5% are not monitored with r2 &amp;gt; 0.8; 24 singletons (most of which were monitored with r2 &amp;gt; 0.6) and 27 SNPs in 9 correlation bins (r2 &amp;gt; 0.8). For the strongest hits, rs10896449, rs12793759 and rs10896438, 26, 6 and 18 SNPs are correlated with r2 &amp;gt; 0.8, respectively. Our results illustrate the complex architecture of the common genetic variants conferring prostate cancer risk on chromosome 11q13. The fine mapping and sequence analysis point towards a subset of SNPs worthy of follow-up studies designed to understand the molecular basis of the susceptibility alleles. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3863.