Background: Breast cancer is the most common malignancy, with a mean age of onset of approximately 60 years. Only a minority of breast cancer patients present with an early onset at or before 40 years of age. An exceptionally young age at diagnosis hints at a possible genetic etiology. Currently, known pathogenic genetic variants only partially explain the disease burden of younger patients. Thus, new knowledge is warranted regarding additional risk variants. In this study, we analyzed DNA repair genes to identify additional variants to shed light on the etiology of early-onset breast cancer. Methods: Germline whole-exome sequencing was conducted in a cohort of 63 patients diagnosed with breast cancer at or before 40 years of age (median 33, mean 33.02, range 23–40 years) with no known pathogenic variants inBRCAgenes. After filtering, all detected rare variants were sorted by pathogenicity prediction scores (CADD score and REVEL) to identify the most damaging genetic changes. The remaining variants were then validated by comparison to a validation cohort of 121 breast cancer patients with no preselected age at cancer diagnosis (mean 51.4 years, range 28–80 years). Analysis of novel exonic variants was based on protein structure modeling. Results: Five novel, deleterious variants in the genesWRN,RNF8,TOP3A,ERCC2, andTREX2were found in addition to a splice acceptor variant inRNF4and two frameshift variants inEXO1andPOLEgenes, respectively. There were also multiple previously reported putative risk variants in other DNA repair genes. Conclusions: Taken together, whole-exome sequencing yielded 72 deleterious variants, including 8 novel variants that may play a pivotal role in the development of early-onset breast cancer. Although more studies are warranted, we demonstrate that young breast cancer patients tend to carry multiple deleterious variants in one or more DNA repair genes.
背景：乳腺癌是最常见的恶性肿瘤，平均发病年龄约为60岁。仅有少数乳腺癌患者在40岁或更年轻时发病。极早的发病年龄提示可能存在遗传病因。目前已知的致病性基因变异仅能部分解释年轻患者的疾病负担。因此，有必要获取关于其他风险变异的新知识。本研究通过分析DNA修复基因以识别更多变异，从而阐明早发性乳腺癌的病因。 方法：对63例确诊年龄在40岁或以下（中位年龄33岁，平均年龄33.02岁，范围23-40岁）且未携带已知BRCA基因致病性变异的乳腺癌患者进行种系全外显子组测序。经过滤后，所有检测到的罕见变异均根据致病性预测评分（CADD评分和REVEL）进行排序，以识别最具破坏性的遗传改变。随后，通过与121例未预设诊断年龄（平均年龄51.4岁，范围28-80岁）的乳腺癌验证队列进行比较，对剩余变异进行验证。新型外显子变异的分析基于蛋白质结构建模。 结果：除在RNF4基因中发现一个剪接受体位点变异，以及在EXO1和POLE基因中分别发现两个移码变异外，还在WRN、RNF8、TOP3A、ERCC2和TREX2基因中发现了五个新的有害变异。此外，在其他DNA修复基因中还发现了多个先前报道的推定风险变异。 结论：全外显子组测序共鉴定出72个有害变异，其中包括8个可能在早发性乳腺癌发展中起关键作用的新变异。尽管需要更多研究加以验证，但本研究表明年轻乳腺癌患者往往携带一个或多个DNA修复基因中的多个有害变异。
肿瘤(癌症)患者之家