Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
J Med Genet. 2017 Nov;54(11):732-741. doi: 10.1136/jmedgenet-2017-104588. Epub 2017 Aug 4.
Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in , , and , we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK.
Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four algorithms.
Truncating variants in (OR=4.69, 95% CI 2.27 to 9.68), (OR=3.26; 95% CI 1.82 to 6.46) and (OR=3.11; 95% CI 2.15 to 4.69), but not (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in and were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in were associated with similar risks for both subtypes. There was also some evidence that missense variants in , and may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect.
Truncating variants in are associated with a higher risk of BC than those in or . A substantial risk of BC due to truncating variants can be excluded.
乳腺癌（BC）是女性最常见的恶性肿瘤，具有主要的遗传性成分。大多数罕见的易感性变异相关风险尚未得到很好的评估。为了更好地描述 、 、 和 中变异的贡献，我们在来自英国东安格利亚的 13087 例 BC 病例和 5488 例对照中对其编码区进行了测序。
通过 PCR 富集基因编码区，进行测序、变异调用和质量过滤。分别估计截断变异携带者和罕见错义变异携带者的 BC 风险，进一步根据四个预测算法的功能域和致病性进行细分。
中的截断变异（OR=4.69，95%CI 2.27 至 9.68）、 （OR=3.26；95%CI 1.82 至 6.46）和 （OR=3.11；95%CI 2.15 至 4.69），但 （OR=0.94；95%CI 0.26 至 4.19）与 BC 风险增加无关。 和 中的截断变异与雌激素受体（ER）阳性疾病的风险相关性更强，而 中的截断变异与两种亚型的风险相关性相似。也有一些证据表明 、 和 中的错义变异可能与 BC 风险有关，但需要更大的研究来量化这种影响的程度。
中的截断变异与 BC 风险的相关性高于 或 中的截断变异。由于截断 变异导致的大量 BC 风险可以排除。
