The contribution of rare alleles to ovarian cancer in the population

描述(申请人提供)：上皮性卵巢癌(EOC)有很大的遗传成分。高外显性易感基因BRCA1和BRCA2的种系突变使70岁前发生EOC的风险约为50%。这些基因是大多数包含多个卵巢癌病例的家系的致病基因；但已知的易感基因在卵巢癌额外的家族风险中所占比例不到40%，这表明其他基因有待发现。我们假设，相当大比例的超额EOC风险是由于编码DNA的中等渗透性、罕见或不常见的功能变异导致终身患病风险的2至10倍。识别更多的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，从而产生重大而快速的临床影响。这个项目分为三个阶段：第一个阶段是发现阶段，我们计划在大约200个非BRCA1/BRCA2 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)项目进行胚系外显子组测序的约400例EOC病例的测序数据，以及正在进行外显子组测序的另外约150个EOC家庭的测序数据。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名来自欧洲的非癌症受试者的外显子组序列分析数据进行比较。接下来是复制阶段，我们计划利用国际合作组织卵巢癌协会联合会(OCAC)的流行病学病例对照收集，在大规模测序和基因分型工作中跟踪第一阶段确定的候选基因和变异。我们将对5,000个卵巢癌病例和5,000个对照中的大约100个基因进行下一代候选基因测序，以表征功能性有害突变的流行程度；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和11,000个外显子测序项目中的另外260,000个罕见变异进行基因分型，以评估它们与疾病的相关性。在最后阶段，我们将对确认的功能变异进行外显性和生存分析，以评估它们的临床意义，这将表明我们识别的基因/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.