Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Hum Mol Genet. 2012 Dec 15;21(24):5373-84. doi: 10.1093/hmg/dds381. Epub 2012 Sep 13.
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
全基因组关联研究（GWAS）对激素受体状态定义的乳腺癌进行了研究，发现了与雌激素受体（ER）阴性亚型易感性相关的基因座。为了确定 ER 阴性乳腺癌的其他遗传变异，我们进行了迄今为止最大的 ER 阴性疾病的荟萃分析，该分析包括来自三个 GWAS 的 4754 例 ER 阴性病例和 31663 例对照：NCI 乳腺和前列腺癌队列联盟（BPC3）（2188 例 ER 阴性病例；25519 例欧洲裔对照），三阴性乳腺癌联盟（TNBCC）（1562 例三阴性病例；3399 例欧洲裔对照）和非裔美国人乳腺癌联盟（AABC）（1004 例 ER 阴性病例；2745 例欧洲裔对照）。我们在另外的 11209 例乳腺癌病例（946 例 ER 阴性病例）和 16057 例日本、拉丁裔和欧洲裔对照中，对 P ≤ 1×10(-5)的 86 个 SNP 进行了基于计算机的复制。我们确定了两个新的乳腺癌易感基因座位于 20q11 和 6q14。20q11 上的 SNP rs2284378 与 ER 阴性乳腺癌（联合两阶段 OR = 1.16；P = 1.1×10(-8))相关，但与整体乳腺癌（OR = 1.08，P = 1.3×10(-6))的相关性较弱，基于 17869 例病例和 43745 例对照，与 ER 阳性疾病（OR = 1.01，P = 0.67）无关联，基于 9965 例病例和 22902 例对照。同样，6q14 上的 rs17530068 与乳腺癌（OR = 1.12；P = 1.1×10(-9))相关，与 ER 阳性（OR = 1.09；P = 1.5×10(-5))和 ER 阴性（OR = 1.16，P = 2.5×10(-7))疾病相关。我们还证实了三个与 ER 阴性（19p13）和 ER 阴性和 ER 阳性乳腺癌（6q25 和 12p11）相关的已知基因座。我们的研究结果强调了大规模合作研究识别新的乳腺癌风险基因座的价值。
