Identifying Ovarian Cancer Susceptibility Alleles using Genome-Wide Scan Data

描述（由申请人提供）：卵巢癌是妇女中第八大最常见的癌症，是妇女癌症相关死亡的第五大最常见原因，也是妇科癌症死亡的主要原因。1年和5年生存率分别只有76%和45%，这主要是由于大多数妇女在诊断时处于晚期。很明显，侵袭性上皮性卵巢癌（卵巢癌）的风险是由遗传和生活方式/生殖因素驱动的。家族史是卵巢癌的重要危险因素；BRCA1和BRCA2突变导致卵巢癌，但仅占该疾病超额家族性风险的约40%，这强烈表明还有其他遗传位点有待发现。许多与卵巢癌相关的风险和保护因素已被确定，包括绝经期激素治疗的使用、会阴滑石粉的使用、肥胖、不孕、胎次、母乳喂养、口服避孕药的使用和输卵管结扎，在这个提案中，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位点的修饰作用，这些基因是通过我们最近完成的全基因组关联研究（GWAS）确定的。在GWAS的第一阶段，我们研究了2000例卵巢癌病例和1500例对照的55万个单核苷酸多态性（snp）。在另外5145例病例和5506例对照中研究了前28219个相关snp，并为所有这些样本编制了流行病学变量的公共数据集。我们将检查这个数据集，寻找基因-生活方式/生殖因素相互作用的证据。此外，我们将精细地绘制出五个区域，这些区域现在已经明确显示出含有卵巢癌易感性等位基因，以确定一组可能的因果变异。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%，其五年生存率为90%。确定新的因果变异以及已知卵巢癌风险和保护因素与遗传变异相互作用的方式，将大大提高我们对这种疾病的理解，并最终提高预防和生存水平。

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.