Haplotype-Based Genome Screen for Ovarian Cancer Loci

描述(申请人提供)：卵巢癌每年在北美妇女中造成的死亡比任何其他妇科癌症都要多。其病因目前知之甚少。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，加起来只占病例的12%-15%。最近的证据表明，细微的(非截断的)但更常见的遗传变异(即群体频率大于5%的单核苷酸多态)会带来更温和的癌症风险增加，并可能涉及相当大比例的病例。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有限，选择合适的候选人是具有挑战性的，迄今为止的努力被证明基本上是不成功的。我们的假设是，卵巢癌易感基因是存在的，但识别它们最有效的策略是全基因组分析。最近的方法和技术发展使这一点成为可能和可行。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DNA和相关风险因素。第一阶段需要使用366,722个单倍型标签(Ht)SNPs来筛选整个基因组，以寻找潜在的感兴趣基因座，使用367例有卵巢癌家族史的病例和479名匹配的对照。第二阶段寻求在303个基于人群的病例和303个配对对照中验证和完善这些结果，使用与风险最密切相关的13,000个SNP。在第三阶段，我们将使用第二阶段的前7309个SNPs来评估我们的结果在3072例患者和3072名匹配对照中的重复性和普适性。这项努力的成功不仅将使我们能够识别出卵巢癌的风险女性，还将阐明这种致命恶性肿瘤的发病机制所涉及的基因。

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.