Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)

卵巢癌遗传关联和相互作用研究 (FOCI) 的随访

• 批准号: 8104223
• 负责人: THOMAS A SELLERS
• 金额: $ 247.89万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-02 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104223
• 关键词: Follow; up; Ovarian; Cancer; Genetic

DESCRIPTION (provided by applicant): Deleterious mutations in BRCA1 and BRCA2 increase ovarian cancer risk substantially, but such mutations are rare in the population and collectively they account for fewer than 15 percent of cases. GWAS have successfully identified many common susceptibility alleles for multiple disease phenotypes, including the identification of genes involved in pathways not previously implicated in cancer. This has not been possible for ovarian cancer, but the recent/imminent completion of several independent GWAS with the potential for replication in participating OCAC studies provides the opportunity to achieve this and match the success for other cancers. In Project 1, the first aim is to pool data from four GWAS that used similar genotyping platforms, use several different approaches to analyze the data, and follow-up the most promising associations (SNPs and CNVs) in a large-scale replication in independent data sets. Genotypes are available from the lllumina HumanHap 610 chip on roughly 4400 cases and 4200 controls through UK and US GWAS, on 500 cases and 300 controls using the lllumina 317k chip, and a pooled DNA analysis of 520 cases and 900 controls in Australia which employed the lllumina 1M beadtype chip. In addition, the UK GWAS has genotyped nearly 22,000 promising SNPs on an additional roughly 5,000 cases and 5,000 controls; and the US GWAS will interrogate 16,000 SNPs on an additional 6,000 cases and 6,000 controls in October 2009. The second aim will be to replicate the findings using a custom iSelect lllumina chip of 13,680 beadtypes on a Stage III study population of an additional roughly 3,500 cases and 3,500 controls that have not been included in any of the previous Stage I or Stage II genotyping efforts. The total estimated three stage sample size will be approximately 16,400 cases and 17,100 controls, providing excellent power to detect risk alleles, critical to Projects 2 and 3. The third aim is to examine the association of SNPs and CNVs from all pooled Stage I and Stage II data in relation to ovarian cancer survival. For aim four we will design and run a custom iSelect lllumina chip of 3,072 SNPs on a Stage HI study population of additional cases for whom overall survival data are available. The total estimated three-stage survival sample size will be approximately 13,700 cases. We will fit ordinal genetic models to predict overall survival accounting for known clinical prognostic factors and conduct exploratory analysis of SNP associations within other major histologic subtypes (e.g., mucinous and clear cell).

BRCA 1和BRCA 2的有害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，它们总共占不到15%的病例。GWAS已经成功地鉴定了多种疾病表型的许多常见易感性等位基因，包括鉴定参与先前未涉及癌症的途径的基因。这对于卵巢癌来说是不可能的，但是最近/即将完成的几项独立的GWAS具有在参与的OCAC研究中复制的潜力，为实现这一目标提供了机会，并与其他癌症的成功相匹配。在项目1中，第一个目标是汇集来自四个GWAS的数据，这些GWAS使用类似的基因分型平台，使用几种不同的方法来分析数据，并在独立数据集中大规模复制中跟踪最有希望的关联（SNP和CNV）。通过英国和美国的GWAS，基因型可从Illumina HumanHap 610芯片获得大约4400例病例和4200例对照，使用Illumina 317 k芯片获得500例病例和300例对照，以及在澳大利亚使用Illumina 1 M珠型芯片对520例病例和900例对照进行合并DNA分析。此外，英国GWAS已经对另外大约5，000例病例和5，000例对照进行了近22，000个有希望的SNP的基因分型;美国GWAS将在2009年10月对另外6，000例病例和6，000例对照进行16，000个SNP的调查。第二个目标是使用13，680种微珠类型的定制iSelect Illumina芯片在III期研究人群中复制研究结果，该研究人群包括额外的约3，500例病例和3，500例对照，这些病例和对照未包括在任何先前的I期或II期基因分型工作中。估计三阶段样本量总计约为16，400例病例和17，100例对照，为检测风险等位基因提供了极好的能力，这对项目2和3至关重要。第三个目的是研究来自所有合并的I期和II期数据的SNP和CNV与卵巢癌生存率的相关性。对于第四个目标，我们将设计并运行具有3，072个SNP的定制iSelect Illumina芯片，用于具有总体存活数据的额外病例的阶段HI研究人群。三阶段生存期样本量估计总数约为13，700例。我们将拟合有序遗传模型来预测已知临床预后因素的总生存率，并对其他主要组织学亚型（例如，粘液和透明细胞）。