Identifying Ovarian Cancer Susceptibility Alleles using Genome-Wide Scan Data

描述（由申请人提供）：卵巢癌是女性第八大常见癌症，女性癌症相关死亡的第五大常见原因，也是妇科癌症死亡的主要原因。一年和五年生存率分别仅为76%和45%，主要是由于大多数女性的诊断晚期。很明显，侵袭性上皮性卵巢癌（卵巢癌）的风险由遗传和生活方式/生殖因素驱动。家族史是卵巢癌的一个强有力的危险因素; BRCA 1和BRCA 2的突变导致卵巢癌，但仅占该疾病的超额家族风险的~40%，强烈表明还有其他遗传位点有待发现。已经确定了许多与卵巢癌相关的风险和保护因素，包括绝经期激素治疗的使用、会阴滑石粉的使用、肥胖、不孕、产次、母乳喂养、口服避孕药的使用和输卵管结扎，在这项提案中，我们有机会在一个非常大的数据集中探索这些和其他生活方式和生殖因素对卵巢癌遗传易感性基因座的修饰作用，这些基因座具有通过我们最近完成的全基因组关联研究（GWAS）确定。在GWAS的第一阶段，我们研究了2000例卵巢癌病例和~1500例对照中的550，000个单核苷酸多态性（SNP）。在另外5，145例病例和5，506例对照中研究了前28，219个相关SNP，我们还为所有这些样本编制了流行病学变量的通用数据集。我们将检查这个数据集的证据，基因-生活方式/生殖因素的相互作用。此外，我们将精细绘制现已明确显示具有卵巢癌易感性等位基因的五个区域，以确定可能的因果变异。这项工作是通过来自世界各地的20多个致力于改善风险预测和早期疾病检测的领先研究小组的合作努力而实现的。在早期阶段被诊断患有卵巢癌的妇女，目前仅占病例的30%，五年生存率为90%。识别新的致病变异以及已知的卵巢癌风险和保护因素与遗传变异相互作用的方式将导致我们对疾病的理解的重大改善，并最终改善预防和生存。 公共卫生相关性：卵巢癌是女性第八大常见癌症，女性癌症相关死亡的第五大常见原因，也是妇科癌症死亡的主要原因;一年和五年生存率分别为微不足道的76%和45%。我们将利用我们的全基因组关联研究（GWAS）在7，145例病例和5，506例对照中产生的数据，以确定13个重要卵巢癌风险和保护因素的基因-环境相互作用。我们还将精细绘制明确显示具有卵巢癌易感性等位基因的五个区域，并解决这些研究中面临的关键方法学挑战。

DESCRIPTION (provided by applicant): Ovarian cancer is the eighth most common cancer in women, the fifth most common cause of cancer-related death in women and the leading cause of gynecological cancer death. One- and five-year survival is only 76% and 45%, respectively, primarily due to the late stage at diagnosis for most women. It is clear that risk of invasive epithelial ovarian cancer (ovarian cancer) is driven by both genetic and lifestyle/reproductive factors. Family history is a strong risk factor for ovarian cancer; mutations in BRCA1 and BRCA2 cause ovarian cancer, but account for only ~40% of the excess familial risk of the disease, strongly suggesting that there are other genetic loci to be discovered. A number of risk and protective factors associated with ovarian cancer have been identified, including menopausal hormone therapy use, perineal talc use, obesity, infertility, parity, breast-feeding, oral contraceptive use, and tubal ligation, In this proposal we have the opportunity to explore in a very large dataset the modifying effects of these and other lifestyle and reproductive factors on ovarian cancer genetic susceptibility loci that have been identified through our recently completed genome-wide association study (GWAS). In stage 1 of our GWAS we have studied 550,000 single nucleotide polymorphisms (SNPs) in 2000 ovarian cancer cases and ~1500 controls. The top 28,219-associated SNPs have been studied in an additional 5,145 cases and 5,506 controls and we have also compiled a common dataset of epidemiological variables for all of these samples. We will examine this dataset for evidence of gene- lifestyle/reproductive factor interactions. In addition, we will fine map the five regions that have now definitively been shown to harbor an ovarian cancer susceptibility allele in order to identify the set of possible causal variants. This work is possible through the collaborative efforts of more than 20 leading research groups from around the world who are committed to improving risk prediction and early stage disease detection. Women diagnosed with ovarian cancer at an early stage, which currently represents only 30% of cases, have a five year survival of 90%. Identifying novel causal variants and the manner in which known ovarian cancer risk and protective factors interact with genetic variants would lead to a major improvement in our understanding of the disease and ultimately improvements in prevention and survival. PUBLIC HEALTH RELEVANCE: Ovarian cancer is the eighth most common cancer in women, the fifth most common cause of cancer-related death in women and the leading cause of gynecological cancer death; one- and five-year survival is a paltry 76% and 45%, respectively. We will utilize the data generated through our genome-wide association study (GWAS) in 7,145 cases and 5,506 controls to identify gene-environment interactions for 13 important ovarian cancer risk and protective factors. We will also fine map the five regions definitively shown to harbor an ovarian cancer susceptibility alleles and address a key methodological challenge faced in studies of these kinds.