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Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer.
Pubmed ID
21531787 (View this publication on the PubMed website)
Hum. Mol. Genet. 2011 Jul; Volume 20 (Issue 14): Pages 2869-78
Chung CC, Ciampa J, Yeager M, Jacobs KB, Berndt SI, Hayes RB, Gonzalez-Bosquet J, Kraft P, Wacholder S, Orr N, Yu K, Hutchinson A, Boland J, Chen Q, Feigelson HS, Thun MJ, Diver WR, Albanes D, Virtamo J, Weinstein S, Schumacher FR, more Cancel-Tassin G, Cussenot O, Valeri A, Andriole GL, Crawford ED, Haiman CA, Henderson BE, Kolonel L, Le Marchand L, Siddiq A, Riboli E, Key TJ, Kaaks R, Isaacs WB, Isaacs SD, Grönberg H, Wiklund F, Xu J, Vatten LJ, Hveem K, Njolstad I, Gerhard DS, Tucker M, Hoover RN, Fraumeni JF, Hunter DJ, Thomas G, Chatterjee N, Chanock SJ
  • Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute/NIH, 8717 Grovemont Circle, Bethesda, MD 20892, USA.

Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 × 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.

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