Jones Michelle R, Kamara Daniella, Karlan Beth Y, Pharoah Paul D P, Gayther Simon A
Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Gynecol Oncol. 2017 Dec;147(3):705-713. doi: 10.1016/j.ygyno.2017.10.001. Epub 2017 Oct 18.
Epithelial ovarian cancer (EOC) is a heterogeneous disease with a major heritable component. The different histotypes of invasive disease - high grade serous, clear cell, endometrioid and mucinous - are associated with different underlying genetic susceptibility and epidemiological and lifestyle risk factors, all of which contribute to the different biology and clinical characteristics of each histotype. A combination of familial and population based sequencing studies, and genome wide association studies (GWAS) have identified a range of genetic susceptibility alleles for EOC comprising rare but highly penetrant genes (e.g. BRCA1, BRCA2) that are responsible for familial clustering of ovarian cancer cases; more moderate penetrance susceptibility genes (e.g. BRIP1, RAD51C/D, MSH6); and multiple common but low penetrance susceptibility alleles identified by GWAS. Identifying genetic risk alleles for ovarian cancer has had a significant impact on disease prevention strategies; for example it is now routine clinical practice for individuals with germline BRCA1 and BRCA2 mutations to undergo risk reducing salpingo-oophorectomy. Because ovarian cancers are commonly diagnosed at a late clinical stage when the prognosis is poor, the continued development of genetic risk prediction and prevention strategies will represent an important approach to reduce mortality due to ovarian cancer. Advances in genomics technologies that enable more high-throughput genetic testing, combined with research studies that identify additional EOC risk alleles will likely provide further opportunities to establish polygenic risk prediction approaches, based on combinations of rare high/moderate penetrance susceptibility genes and common, low penetrance susceptibility alleles. This article reviews the current literature describing the genetic and epidemiological components of ovarian cancer risk, and discusses both the opportunities and challenges in using this information for clinical risk prediction and prevention.
上皮性卵巢癌（EOC）是一种具有主要遗传成分的异质性疾病。侵袭性疾病的不同组织学类型——高级别浆液性、透明细胞、子宫内膜样和黏液性——与不同的潜在遗传易感性以及流行病学和生活方式风险因素相关，所有这些因素都导致了每种组织学类型不同的生物学特性和临床特征。基于家族和人群的测序研究以及全基因组关联研究（GWAS）的结合，已经确定了一系列EOC的遗传易感性等位基因，包括导致卵巢癌病例家族聚集的罕见但高度显性的基因（如BRCA1、BRCA2）；中等显性易感性基因（如BRIP1、RAD51C/D、MSH6）；以及GWAS确定的多个常见但低显性易感性等位基因。确定卵巢癌的遗传风险等位基因对疾病预防策略产生了重大影响；例如，对于携带种系BRCA1和BRCA2突变的个体，进行降低风险的输卵管卵巢切除术现在已成为常规临床实践。由于卵巢癌通常在临床晚期被诊断出来，此时预后较差，因此遗传风险预测和预防策略的持续发展将是降低卵巢癌死亡率的重要方法。基因组技术的进步使得能够进行更高通量的基因检测，再加上识别其他EOC风险等位基因的研究，可能会提供更多机会，基于罕见的高/中等显性易感性基因和常见的低显性易感性等位基因的组合，建立多基因风险预测方法。本文综述了描述卵巢癌风险的遗传和流行病学成分的当前文献，并讨论了利用这些信息进行临床风险预测和预防的机遇与挑战。
