Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

中文翻译：

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全基因组关联研究从整体和亚型特异性分析中确定了 32 个新的乳腺癌易感位点。


乳腺癌易感性变异经常表现出与肿瘤亚型 1-3 相关的异质性。为了确定新的位点，我们进行了一项全基因组关联研究，包括 133,384 例乳腺癌病例和 113,789 例对照，以及 18,908 名欧洲血统的 BRCA1 突变携带者（其中 9,414 名患有乳腺癌），使用标准和新颖的方法来解释潜在的肿瘤异质性：雌激素受体、孕激素受体和人表皮生长因子受体2的状态和肿瘤分级。我们确定了 32 个新的易感位点 (P < 5.0 × 10-8)，其中 15 个显示出与至少一种肿瘤特征相关的证据（错误发现率 < 0.05）。五个位点显示管腔亚型和非管腔亚型之间呈相反方向的关联（P < 0.05）。计算机分析表明，这五个位点包含正常管腔细胞和基底乳腺细胞之间不同的细胞特异性增强子。五个内在样亚型之间的遗传相关性范围为 0.35 至 0.80。由所有已知易感位点解释的全基因组芯片遗传率对于管腔 A 样疾病为 54.2%，对于三阴性疾病为 37.6%。对于管腔 A 样疾病和三阴性疾病，多基因风险评分（包括 330 个变异）最高 1% 的分位数与中间分位数的比值比分别为 5.63 和 3.02。这些发现加深了对乳腺癌亚型遗传易感性的了解，并将为亚型特异性多基因风险评分的制定提供信息。