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）具有实质性的遗传成分。高外显率易感基因BRCA1和BRCA2的种系突变导致70岁时EOC的风险约为50%。这些基因是导致大多数家庭有几个EOC病例的原因；但已知易感基因占EOC超额家族风险的不到40%，这表明其他基因有待发现。我们假设相当大比例的过度EOC风险是由于编码DNA中中等渗透性，罕见或不常见的功能变异，赋予2至10倍的终生疾病风险。通过更好的风险预测和预防策略，以及开发新的治疗方法和个性化治疗，确定额外的EOC易感基因可以降低疾病相关死亡率，从而产生重大而迅速的临床影响。该项目分为三个阶段：第一个阶段是发现阶段，我们计划对约200个非brca1 /BRCA2 EOC家族进行外显子组测序，以表征这些家族中功能编码突变的基因组谱。我们还将利用约400例EOC病例的测序数据，这些病例已经通过癌症基因组图谱（TCGA）项目进行了种系外显子组测序，另外约150例EOC家族的外显子组测序正在进行中。然后，我们将把我们发现的候选功能变异的频率与来自多个不同研究的约16,000名欧洲非癌症受试者的联合外显子组序列分析数据进行比较。接下来是复制阶段，我们计划通过大规模测序和基因分型工作，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收集，追踪在第一阶段确定的候选基因和变异。我们将在5000例EOC病例和5000例对照中对大约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对另外260,000个罕见变异进行基因分型，在5,000个EOC病例和5,000个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异进行外显率和生存分析，以评估其临床意义，这将表明我们鉴定的基因/变异的直接临床价值。

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.