Kirchhoff Tomas, Chen Zhang-qun, Gold Bert, Pal Prodipto, Gaudet Mia M, Kosarin Kristi, Levine Douglas A, Gregersen Peter, Spencer Sara, Harlan Megan, Robson Mark, Klein Robert J, Hudis Clifford A, Norton Larry, Dean Michael, Offit Kenneth
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2468-75. doi: 10.1158/1055-9965.EPI-09-0151. Epub 2009 Aug 18.
Recently, we identified a novel breast cancer susceptibility locus at 6q22.33 following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on 6q22.33 (rs2180341) in an additional 487 Ashkenazi Jewish breast cancer cases and in an independent non-Jewish, predominantly European American, population of 1,466 breast cancer cases and 1,467 controls. We confirmed the 6q22.33 association with breast cancer risk in the replication cohorts [per-allele odds ratio (OR), 1.18; 95% confidence interval (95% CI), 1.04-1.33; P = 0.0083], with the strongest effect in the aggregate meta-analysis of 3,039 breast cancer cases and 2,616 Ashkenazi Jewish and non-Jewish controls (per-allele OR, 1.24; 95% CI, 1.13-1.36; P = 3.85 x 10(-7)). We also showed that the association was slightly stronger with estrogen receptor-positive tumors (per-allele OR, 1.35; 95% CI, 1.20-1.51; P = 2.2 x 10(-5)) compared with estrogen receptor-negative tumors (per-allele OR, 1.19; 95% CI, 0.97-1.47; P = 0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in breast cancer susceptibility. Due to the stronger association of 6q22.33 with estrogen receptor-positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed RNF146 in the MCF-7 breast cancer cell line, we observed diminished expression of an estrogen receptor response element reporter construct. This study confirms the association of 6q22.33 with breast cancer, with slightly stronger effect in estrogen receptor-positive tumors. Further functional studies of candidate genes are in progress, and a large replication analysis is being completed as part of an international consortium.
最近，在对德系犹太人遗传隔离群进行全基因组关联研究后，我们在6q22.33区域鉴定出一个新的乳腺癌易感位点。为了重复这些研究结果，我们对另外487例德系犹太人乳腺癌病例以及一个独立的、以欧美裔为主的非犹太人群中的1466例乳腺癌病例和1467例对照，就6q22.33（rs2180341）进行了病例对照关联分析。我们在重复队列中证实了6q22.33与乳腺癌风险的关联[等位基因优势比（OR）为1.18；95%置信区间（95%CI）为1.04 - 1.33；P = 0.0083]，在对3039例乳腺癌病例以及2616例德系犹太人和非犹太对照进行的汇总荟萃分析中效应最强（等位基因OR为1.24；95%CI为1.13 - 1.36；P = 3.85×10⁻⁷）。我们还表明，与雌激素受体阴性肿瘤（等位基因OR为1.19；95%CI为0.97 - 1.47；P = 0.1）相比，该关联在雌激素受体阳性肿瘤中略强（等位基因OR为1.35；95%CI为1.20 - 1.51；P = 2.2×10⁻⁵）。此外，本研究为6q22.33在乳腺癌易感性中的功能意义提供了新的见解。由于6q22.33与雌激素受体阳性乳腺癌的关联更强，我们研究了候选基因对雌激素受体反应元件的影响。在MCF - 7乳腺癌细胞系中过表达RNF146后，我们观察到雌激素受体反应元件报告基因构建体的表达降低。本研究证实了6q22.33与乳腺癌有关，在雌激素受体阳性肿瘤中的效应略强。对候选基因的进一步功能研究正在进行中，作为一个国际联盟的一部分，一项大规模的重复分析也即将完成。
