Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, NordLab Oulu, University of Oulu, Oulu, Finland.
Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland.
Eur J Cancer. 2021 Jan;143:46-51. doi: 10.1016/j.ejca.2020.10.033. Epub 2020 Dec 3.
Breast cancer is strongly influenced by hereditary risk factors. Yet, the known susceptibility genes and genomic loci explain only about half of the familial component of the disease. To identify novel breast cancer predisposing gene defects, here we have performed massive parallel sequencing for Northern Finnish breast cancer cases.
Ninety-eight breast cancer cases with indication of hereditary disease susceptibility were exome sequenced. Data filtering strategy focused on predictably deleterious rare variants that were still enriched in the sequenced cohort. Findings were confirmed with additional, geographically matched breast cancer cohorts.
A recurrent heterozygous splice acceptor variant, c.918-1G>C, in SERPINA3, was identified, and it was significantly enriched both in the hereditary (6/201, 3.0%, p = 0.006, OR 5.1, 95% CI 1.7-14.8) and unselected breast cancer cohort (26/1569, 1.7%, p = 0.009, OR 2.8, 95% CI 1.3-6.2). SERPINA3 c.918-1G>C carriers were also significantly more likely to have a rare tumor subtype, medullary breast cancer, than the non-carriers (4/26, 15.4%, p = 0.000014, OR 42.9, 95% CI 11.7-157.1).
These findings demonstrate that c.918-1G>C germline variant in SERPINA3 gene, encoding a member of the serine protease inhibitor class, is a novel breast cancer predisposing allele.
乳腺癌受遗传风险因素的强烈影响。然而，已知的易感基因和基因组位点仅能解释该疾病家族成分的约一半。为了鉴定新的乳腺癌易感基因缺陷，我们对来自芬兰北部的乳腺癌病例进行了大规模平行测序。
对 98 例具有遗传性疾病易感性指征的乳腺癌病例进行外显子组测序。数据过滤策略侧重于预测性有害的罕见变异，这些变异在测序队列中仍然富集。通过额外的、地理匹配的乳腺癌队列对发现结果进行了确认。
鉴定出 SERPINA3 中存在一个反复出现的杂合剪接受体变异 c.918-1G>C，该变异在遗传性（6/201，3.0%，p=0.006，OR 5.1，95%CI 1.7-14.8）和未选择的乳腺癌队列（26/1569，1.7%，p=0.009，OR 2.8，95%CI 1.3-6.2）中均显著富集。SERPINA3 c.918-1G>C 携带者也更有可能患有罕见的肿瘤亚型——髓样乳腺癌，而非携带者（4/26，15.4%，p=0.000014，OR 42.9，95%CI 11.7-157.1）。
这些发现表明，SERPINA3 基因中的 c.918-1G>C 种系变异，该基因编码丝氨酸蛋白酶抑制剂家族的成员，是一种新的乳腺癌易感等位基因。
