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.
Hum Mol Genet. 2011 Jul 15;20(14):2869-78. doi: 10.1093/hmg/ddr189. Epub 2011 Apr 29.
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.
全基因组关联研究已经确定了位于 11q13 染色体上的前列腺癌易感等位基因。作为癌症遗传易感标记物（CGEMS）计划的一部分，在来自欧洲的 10272 例病例和 9123 例对照（10 项研究）中，使用通过使用 HapMap SNP 进行两阶段标记策略选择的 120 个常见单核苷酸多态性（SNP）对最显著标记 rs10896449 侧翼区域进行了精细映射。单基因座分析确定了 18 个低于全基因组显著性水平（P<10(-8)）的 SNP，其中 rs10896449 最为显著（P=7.94×10(-19)）。包含显著 SNP 的多基因座模型依次在 rs12793759 处鉴定出第二个关联[比值比（OR）=1.14，P=4.76×10(-5)，调整后 P=0.004]，该关联独立于 rs10896449，并且在该区域内进行多次测试调整后仍然显著。检测到与先前报道的 rs12418451（r(2)=0.96）独立的 rs10896438 （OR=1.07，P=5.92×10(-3)，调整后 P=0.054），该 SNP 是 rs10896449 和 rs12793759 的替代物。我们观察到一个重组热点，将 rs10896438 与 rs10896449 和 rs12793759 分开，并且低连锁不平衡（rs10896449-rs12793759，r(2)=0.17；rs10896449-rs10896438，r(2)=0.10；rs12793759-rs10896438，r(2)=0.12）证实了我们发现的三个独立信号。通过对来自欧洲的 63 名对照者的约 123kb 进行下一代测序，对 1000 个基因组和 HapMap 数据进行标记 SNP 的分析，我们观察到了三个独立信号的多个替代标记，这些信号由 rs10896449（n=31）、rs10896438（n=24）和 rs12793759（n=8）标记。我们的结果表明，在 11q13 导致前列腺癌风险的常见变异体的复杂结构。我们估计，在未来旨在研究多个关联信号的生物学基础的研究中，应考虑至少 63 个常见变体。
