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。病因学知之甚少。虽然BRCA 1和BRCA 2的高度外显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，总共只占12-15%的病例。最近的证据表明，微妙的（非截短），但更常见的遗传变异（即单核苷酸多态性大于5%的人口频率）赋予更温和的癌症风险增加，并可能参与了显着比例的情况下。然而，迄今为止进行的大多数研究往往广泛依赖于候选基因的方法。由于目前对卵巢癌病理生物学的了解有限，因此选择合适的候选人具有挑战性，迄今为止的努力基本上是不成功的。我们的假设是，卵巢癌易感基因存在，但最富有成效的战略，他们的鉴定是全基因组分析。最近的方法和技术发展使这成为可能和可行。我们的方法将是联合收割机的资源和专业知识的四个大型病例对照研究卵巢癌，已收集基因组DNA和相关的危险因素的参与者。第一阶段需要使用366，722个单倍型标记（ht）SNP来筛选整个基因组的潜在基因座，使用367个具有卵巢癌家族史的病例和479个匹配的对照。第二阶段试图验证和完善这些结果，在303个基于人群的病例和303个匹配的对照中使用13,000个与风险最密切相关的SNP。在第三阶段，我们将使用第二阶段的前7309个SNP，在3072例病例和3072例匹配对照中评估我们结果的可重复性和可推广性。这一奋进的成功不仅可以识别卵巢癌风险的妇女，而且还将阐明这种致命恶性肿瘤发病机制中涉及的基因。

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.