Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Hum Mol Genet. 2011 Dec 1;20(23):4693-706. doi: 10.1093/hmg/ddr368. Epub 2011 Aug 18.
A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.
一项全基因组关联研究（GWAS）鉴定出位于 1p11.2 和 14q24.1（RAD51L1）的单核苷酸多态性（SNP）是乳腺癌易感性位点。最初的 GWAS 表明，这两个位点对雌激素受体（ER）阳性肿瘤的影响更强。利用乳腺癌协会联盟（BCAC）的数据，我们试图确定风险是否因 ER、孕激素受体（PR）、人表皮生长因子受体 2（HER2）、分级、淋巴结状态、肿瘤大小以及导管或小叶形态而不同。我们对 1p11.2 上的 rs11249433 以及 14q24.1（RAD51L1）上的两个高度相关的 SNPrs999737 和 rs10483813（r²=0.98）进行了基因分型，这些 SNP 共用于 39 项研究中的 46036 例浸润性乳腺癌病例和 46930 例对照。按肿瘤特征进行的分析主要针对报告为白种欧洲血统女性的受试者，基于 25458 例病例，其中 87%有 ER 数据。位于 1p11.2 的 SNP 与 ER 阳性肿瘤的相关性明显更强[ER 阳性肿瘤的每等位基因优势比（OR）为 1.13，95%置信区间（CI）为 1.10-1.16，而 ER 阴性肿瘤的 OR 为 1.03，95%CI 为 0.98-1.07，仅病例异质性 P=7.6×10（-5）]。该 SNP 与低分级肿瘤（仅病例 P=6.7×10（-3））和小叶组织学肿瘤（仅病例 P=0.01）的相关性更强。14q24.1 上的 SNP 与评估的大多数肿瘤亚型的风险相关，包括三阴性乳腺癌，这以前尚未描述过。我们的结果强调了需要进行大型的肿瘤病理数据汇集研究，以帮助细化与不同乳腺癌亚型易感性相关的 SNP 关联的风险估计。
