Haplotype-Based Genome Screen for Ovarian Cancer Loci

描述（由申请人提供）：卵巢癌每年在北美妇女中造成的死亡人数超过任何其他妇科癌症。病因尚不清楚。虽然已知BRCA1和BRCA2的高渗透性突变会显著增加卵巢癌的风险，但这种突变在人群中很少见，总的来说它们只占病例的12-15%。最近的证据表明，微妙的（非截断的）但更常见的遗传变异（即大于5%人群频率的单核苷酸多态性）会增加癌症风险，并且可能与很大比例的病例有关。然而，迄今为止进行的大多数研究都倾向于广泛依赖候选基因方法。由于目前对卵巢癌病理生物学的了解是有限的，因此选择合适的候选药物是具有挑战性的，迄今为止的努力在很大程度上是不成功的。我们的假设是卵巢癌易感基因是存在的，但最有效的鉴定策略是全基因组分析。最近的方法和技术发展使这成为可能和可行的。我们的方法将是结合四个大型卵巢癌病例对照研究的资源和专业知识，这些研究收集了参与者的基因组DMA和相关风险因素。第一阶段需要使用366,722单倍型标记（ht） snp来筛选整个基因组中潜在的感兴趣位点，使用367例有卵巢癌家族史的病例和479例匹配对照。II期研究旨在利用13000个与风险最密切相关的snp，在303个基于人群的病例和303个匹配的对照中验证和完善这些结果。在III期研究中，我们将使用来自II期的前7309个snp，在3072例病例和3072个匹配对照中评估结果的可重复性和普遍性。这一努力的成功不仅将使识别有卵巢癌风险的妇女，而且将阐明与这种致命恶性肿瘤发病机制有关的基因。

DESCRIPTION (provided by applicant): Ovarian cancer causes more deaths each year among North American women than any other gynecologic cancer. The etiology is poorly understood. Although highly penetrant mutations in BRCA1 and BRCA2 are known to significantly increase ovarian cancer risk, such mutations are rare in the population and collectively they account for only 12-15% of cases. Recent evidence suggests that subtle (non-truncating) but more common genetic variants (i.e. single nucleotide polymorphisms with greater than 5% population frequency) confer more moderate increased risks of cancer and are likely to be involved in a significant proportion of cases. However, most studies conducted to date have tended to rely extensively on candidate gene approaches. Because current understanding of the pathobiology of ovarian cancer is limited, selection of appropriate candidates is challenging and efforts to date have proven largely unsuccessful. Our hypothesis is that ovarian cancer susceptibility genes exist but that the most fruitful strategy for their identification is a genome-wide analysis. Recent methodological and technical developments make this possible and feasible. Our approach will be to combine the resources and expertise of four large case control studies of ovarian cancer that have collected genomic DMA and relevant risk factors on participants. Phase I entails the use of 366,722 haplotype-tagging (ht) SNPs to screen the entire genome for potential loci of interest using 367 cases with a family history of ovarian cancer and 479 matched controls. Phase II seeks to validate and refine these results among 303 population-based cases and 303 matched controls using the 13,000 SNPs most strongly associated with risk. In Phase III we will assess the reproducibility and generalizability of our results among 3072 cases and 3072 matched controls, using the top 7309 SNPs from Phase II. Success in this endeavor will not only allow identification of women at risk for ovarian cancer, but will elucidate genes involved in the pathogenesis of this deadly malignancy.