The contribution of rare alleles to ovarian cancer in the population

描述（由申请人提供）：上皮性卵巢癌（EOC）具有相当大的遗传成分。高转移率易感基因BRCA 1和BRCA 2的生殖系突变赋予70岁时EOC风险约50%。这些基因是负责大多数家庭包含几个案件的EOC，但已知的易感基因占不到40%的过度家族风险的EOC表明，其他基因等待发现。我们假设，EOC风险的很大一部分是由于编码DNA中的中度渗透性、罕见或不常见的功能变异，这些变异赋予2至10倍的疾病终生风险。鉴定其他EOC易感基因可以通过更好的风险预测-预防策略降低疾病相关死亡率，并开发新的治疗方法和个性化治疗，从而产生重大和快速的临床影响。该项目分为三个阶段：第一阶段是发现阶段，我们计划在约200个非BRCA 1/BRCA 2 EOC家族中进行外显子组测序，以表征这些家族中基因组广泛的功能编码突变。我们还将利用通过癌症基因组图谱（TCGA）项目进行生殖系外显子组测序的约400个EOC病例的测序数据，以及另外约150个正在进行外显子组测序的EOC家族。然后，我们将比较我们发现的候选功能变体的频率与来自多项不同研究的约16，000名欧洲非癌症受试者的组合外显子组序列分析的数据。接下来，是一个复制阶段，我们计划在大规模测序和基因分型工作中，利用国际合作组织卵巢癌协会联盟（OCAC）的流行病学病例对照集，对第1阶段确定的候选基因和变体进行随访。我们将对5，000例EOC病例和5，000例对照中的约100个基因进行候选基因下一代测序，以表征功能性有害突变的患病率;对于我们确定的约20，000个非同义罕见变异，我们将使用定制的阵列对这些变异进行基因分型，并从11，000个外显子组测序项目中获得另外260，000个罕见变异，在5,000例EOC病例和5,000例对照中评估其疾病相关性。在最后阶段，我们将对确认的功能变体进行生存率和生存分析，以评估其临床意义，这将表明我们鉴定的基因/变体的直接临床价值。

DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) has a substantial hereditary component. Germline mutations in the high- penetrance susceptibility genes BRCA1 and BRCA2 confer EOC risks of around 50% by age 70. These genes are responsible for most families containing several cases of EOC; but the known susceptibility genes account for less than 40% of the excess familial risk of EOC indicating that other genes await discovery. We hypothesize that a substantial proportion of the excess EOC risk is due to moderately penetrant, rare or uncommon functional variants in coding DNA conferring 2 to 10 fold lifetime risks of disease. Identifying additional EOC susceptibility genes could have a major and rapid clinical impact by reducing disease associated mortality through better risk prediction-prevention strategies, and developing novel therapeutic approaches and individualized treatments. There are three phases to this project: The first is a discovery phase, in which we plan to perform exome sequencing in ~200 non-BRCA1/BRCA2 EOC families to characterize the genome wide spectrum of functional coding mutations in these families. We will also leverage sequencing data from ~400 EOC cases that have undergone germline exome sequencing through The Cancer Genome Atlas (TCGA) project, and another ~150 EOC families for whom exome sequencing is ongoing. We will then compare the frequency of candidate functional variants we find with data from a combined exome sequence analysis of ~16,000 non-cancer subjects of European origin from multiple different studies. Next, is a replication phase in which we plan to follow-up candidate genes and variants identified in phase 1, in large-scale sequencing and genotyping efforts, leveraging the epidemiological case-control collections of an international collaboration, the Ovarian Cancer Association Consortium (OCAC). We will perform candidate gene next generation sequencing for approximately 100 genes in 5,000 EOC cases and 5,000 controls to characterize the prevalence of functional deleterious mutations; and for ~20,000 non-synonymous rare variants we identify we will use a customized array to genotype these variants and an additional 260,000 rare variants from the 11,000 exome sequencing project, in 5,000 EOC cases and 5,000 controls to evaluate their disease associations. In the final phase, we will perform penetrance and survival analyses for confirmed functional variants to evaluate their clinical significance, which will indicate the immediate clinical value of the genes/variants we identify.