Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Hum Mol Genet. 2011 Aug 15;20(16):3304-21. doi: 10.1093/hmg/ddr226. Epub 2011 May 18.
Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
两个单核苷酸多态性（SNPs）位于 6q25.1 附近的 ESR1 基因，已被证实与亚洲人（rs2046210）和欧洲人的乳腺癌易感性有关（rs9397435）。在欧洲进行的全基因组关联研究确定了另外两个乳腺癌易感性变体：rs11249433 在 1p11.2 处和 rs999737 在 RAD51L1 处的 14q24.1。尽管先前确定的乳腺癌易感性变体已被证明与 BRCA1 和 BRCA2 突变携带者的乳腺癌风险相关，但这些 SNP 与突变携带者的乳腺癌易感性的关系目前尚不清楚。为了解决这个问题，我们在来自 Consortium of Investigators of Modifiers of BRCA1/2 的 42 项研究中的 42 项研究中的 BRCA1 和 BRCA2 突变携带者中对这些 SNP 进行了基因分型。在对 14,312 名 BRCA1 和 8,053 名 BRCA2 欧洲血统突变携带者的分析中，6q25.1 SNPs（r² = 0.14）独立与 BRCA1 突变携带者的乳腺癌风险相关[风险比（HR）= 1.17，95%置信区间（CI）：1.11-1.23，P-trend = 4.5×10（-9）为 rs2046210；HR = 1.28，95%CI：1.18-1.40，P-trend = 1.3×10（-8）为 rs9397435]，但只有 rs9397435 与 BRCA2 携带者的风险相关（HR = 1.14，95%CI：1.01-1.28，P-trend = 0.031）。SNP rs11249433（1p11.2）与 BRCA2 突变携带者的乳腺癌风险相关（HR = 1.09，95%CI：1.02-1.17，P-trend = 0.015），但与 BRCA1 突变携带者的乳腺癌风险无关（HR = 0.97，95%CI：0.92-1.02，P-trend = 0.20）。SNP rs999737（RAD51L1）与 BRCA1 或 BRCA2 突变携带者的乳腺癌风险无关（P-trend = 0.27 和 0.30）。确定与 BRCA1 突变携带者的乳腺癌风险相关的 6q25.1 处的 SNPs 将有助于更好地了解这些女性肿瘤发展的生物学。
