We performed a genome-wide association analysis in the Women\'s Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated.
The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.
结果:我们在妇女环境癌症和放射流行病学(WECARE)研究中进行了全基因组关联分析,研究对象为年龄<55岁的首次诊断为乳腺癌的女性,包括1161例CBC和1668例单侧乳腺癌(UBC)作为对照。我们观察到两个基因座(rs59657211,9q32,SLC31A2/FAM225A和rs3815096,6p22.1,TRIM31),提示全基因组显着关联(P<1×10-6)。我们还发现与乳腺癌特异性多基因风险评分(PRS)相关的CBC风险增加,该评分包含239个已知的乳腺癌易感性单核苷酸多态性(SNP)(每1-SD变化的比率:1.25;95%置信区间1.14-1.36,P<0.0001)。化疗对CBC风险的保护作用仅在PRS升高的患者中具有统计学意义(P异质性=0.04)。包括PRS和已知乳腺癌危险因素的AUC显著升高。
结论:目前的GWAS鉴定了两个以前未报告的基因座,具有全基因组意义。我们还证实,CBC风险升高与独立于已知乳腺癌风险因素的全面乳腺癌易感性PRS相关。这些发现促进了我们对涉及CBC病因的遗传风险因素的理解。