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大规模测序确定乳腺癌和卵巢癌与 已知和未知癌症易感基因的相关性 自从乳腺癌易感基因BRCA1和BRCA2被发现之后，多种外显率较高的基因相继被报告为遗传性乳腺癌或卵巢癌的风险因素；不过，这些发现能否代表乳腺癌或卵巢癌的完整基因谱？哪些非BRCA基因与乳腺癌或卵巢癌风险相关？风险大小如何？ 2018年8月16日，《美国医学会杂志》肿瘤学分册在线发表安布瑞基因、先声药业、腾邦生物技术、英特利亚医疗、尔湾加利福尼亚大学的研究报告，通过大规模测序确定了乳腺癌或卵巢癌与已知和未知易感基因的相关性。 该研究标本来自2014～2015年美国各地1200家医院诊所转诊接受基因检测的1万1416例乳腺癌或卵巢癌患者、3988例无癌对照者，进行全外显子组测序，并检查基因与表型的相关性。此外，将《基因组聚集数据库》作为参考对照进行病例对照分析。主要结局衡量指标：625个癌症易感基因的乳腺癌风险相关致病变异、已知乳腺癌或卵巢癌易感基因与乳腺癌亚型（导管浸润、小叶浸润、激素受体阳性、激素受体阴性、男性、早发）的相关性。 结果发现，乳腺癌患者9639例，其中早发乳腺癌（诊断时≤45岁）3960例（41.1%）、男性乳腺癌123例（1.3%），男性与女性相比，诊断时年龄较大（平均年龄：61.8±12.8比48.6±11.4岁）。卵巢癌女性2051例，其中诊断时≤45岁445例（21.7%）。 以下4个非BRCA基因变异与乳腺癌风险增加相关：
以下4个非BRCA基因变异与卵巢癌风险增加相关：
MRN复合基因和CDKN2A均与乳腺癌或卵巢癌风险增加无关。该研究结果也不支持既往报告的乳腺癌与卵巢癌相关易感基因BRIP1、RAD51C、RAD51D或错配修复基因MSH2和PMS2的相关性。 因此，该研究对患者和对照者进行的大规模外显子组测序结果，揭示了迄今为止已知和未知非BRCA易感基因与乳腺癌或卵巢癌的相关性，以及其他可能参与DNA修复和基因组维护的乳腺癌或卵巢癌候选易感基因。 对此，英国南安普顿大学、南安普顿大学医院、安妮公主医院的肿瘤学和遗传学专家发表特邀评论：基因时代的遗传性乳腺癌和卵巢癌检测。 JAMA Oncol. 2018 Aug 16. [Epub ahead of print] Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing. Hsiao-Mei Lu, Shuwei Li, Mary Helen Black, Shela Lee, Robert Hoiness, Sitao Wu, Wenbo Mu, Robert Huether, Jefferey Chen, Srijani Sridhar, Yuan Tian, Rachel McFarland, Jill Dolinsky, Brigette Tippin Davis, Sharon Mexal, Charles Dunlop, Aaron Elliott. Ambry Genetics, Aliso Viejo, California; Simcere Pharmaceutical, Jiangsu, China; Tempus, Chicago, Illinois; Intellia Therapeutics, Cambridge, Massachusetts; University of California, Irvine. This study of patients with breast cancer, ovarian cancer, or both compared with controls uses whole-exome sequencing to investigate whether non-BRCA genes are associated with an increased risk of those cancers. QUESTION: Which non-BRCA genes are associated with breast or ovarian cancer and what are the magnitudes of those risks? FINDINGS: In this study assessing whole-exome sequencing results from 11416 patients with breast cancer, ovarian cancer, or both and 3988 controls, an increased risk of breast cancer was associated with PALB2, ATM, CHEK2, and MSH6 genes, whereas MSH6, RAD51C, TP53, and ATM genes were associated with an increased risk of ovarian cancer. MEANING: In addition to confirming several well-known breast or ovarian cancer gene associations, this study identified MSH6 and ATM as possible moderate-risk breast and ovarian cancer predisposition genes, respectively. IMPORTANCE: Since the discovery of BRCA1 and BRCA2, multiple high- and moderate-penetrance genes have been reported as risk factors for hereditary breast cancer, ovarian cancer, or both; however, it is unclear whether these findings represent the complete genetic landscape of these cancers. Systematic investigation of the genetic contributions to breast and ovarian cancers is needed to confirm these findings and explore potentially new associations. OBJECTIVE: To confirm reported and identify additional predisposition genes for breast or ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: In this sample of 11416 patients with clinical features of breast cancer, ovarian cancer, or both who were referred for genetic testing from 1200 hospitals and clinics across the United States and of 3988 controls who were referred for genetic testing for noncancer conditions between 2014 and 2015, whole-exome sequencing was conducted and gene-phenotype associations were examined. Case-control analyses using the Genome Aggregation Database as a set of reference controls were also conducted. MAIN OUTCOMES AND MEASURES: Breast cancer risk associated with pathogenic variants among 625 cancer predisposition genes; association of identified predisposition breast or ovarian cancer genes with the breast cancer subtypes invasive ductal, invasive lobular, hormone receptor-positive, hormone receptor-negative, and male, and with early-onset disease. RESULTS: Of 9639 patients with breast cancer, 3960 (41.1%) were early-onset cases (≤45 years at diagnosis) and 123 (1.3%) were male, with men having an older age at diagnosis than women (mean [SD] age, 61.8 [12.8] vs 48.6 [11.4] years). Of 2051 women with ovarian cancer, 445 (21.7%) received a diagnosis at 45 years or younger. Enrichment of pathogenic variants were identified in 4 non-BRCA genes associated with breast cancer risk: ATM (odds ratio [OR], 2.97; 95% CI, 1.67-5.68), CHEK2 (OR, 2.19; 95% CI, 1.40-3.56), PALB2 (OR, 5.53; 95% CI, 2.24-17.65), and MSH6 (OR, 2.59; 95% CI, 1.35-5.44). Increased risk for ovarian cancer was associated with 4 genes: MSH6 (OR, 4.16; 95% CI, 1.95-9.47), RAD51C (OR, not estimable; false-discovery rate-corrected P=.004), TP53 (OR, 18.50; 95% CI, 2.56-808.10), and ATM (OR, 2.85; 95% CI, 1.30-6.32). Neither the MRN complex genes nor CDKN2A was associated with increased breast or ovarian cancer risk. The findings also do not support previously reported breast cancer associations with the ovarian cancer susceptibility genes BRIP1, RAD51C, and RAD51D, or mismatch repair genes MSH2 and PMS2. CONCLUSIONS AND RELEVANCE: The results of this large-scale exome sequencing of patients and controls shed light on both well-established and controversial non-BRCA predisposition gene associations with breast or ovarian cancer reported to date and may implicate additional breast or ovarian cancer susceptibility gene candidates involved in DNA repair and genomic maintenance. DOI: 10.1001/jamaoncol.2018.2956 JAMA Oncol. 2018 Aug 16. [Epub ahead of print] Hereditary Breast and Ovarian Cancer Testing in the Genomic Era. Stephanie L. Greville-Heygate, Diana M. Eccles, Lucy E. Side. University of Southampton, University Hospital Southampton, Southampton, United Kingdom; Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom. DOI: 10.1001/jamaoncol.2018.3034
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