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: 8504772
• 负责人: THOMAS A SELLERS
• 金额: $ 208.43万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504772
• 关键词: Accounting; Alleles; Australia; BRCA1 gene; BRCA2 gene; Biology; Clear Cell; Clinical; Custom; DNA analysis; Data; Data Analyses; Data Set; Disease; Early Diagnosis; Genes; Genetic; Genetic Models; Genotype; High Risk Woman; Histologic; Knowledge; Malignant Neoplasms; Malignant neoplasm of ovary; Medicine; Meta-Analysis; Mucinous; Mutation; Pathway interactions; Population; Population Study; Predisposition; Prevention; Prognostic Factor; Risk; Running; Sample Size; Staging; cancer genetics; cancer risk; design; disease phenotype; follow-up; genetic association; genome wide association study; new therapeutic target; success

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).

描述（由申请人提供）：BRCA1和BRCA2中有害突变大大增加了卵巢癌的风险，但是这种突变在人群中很少见，并且总共占病例的不到15％。 GWAS成功地识别了许多对多种疾病表型的常见易感性等位基因，包括鉴定涉及以前与癌症有关的途径的基因。这对于卵巢癌不可能，但是最近/即将完成几个独立的GWAS，有可能复制参加OCAC研究，这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，第一个目的是从四个使用类似基因分型平台的GWA的数据汇总数据，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进最有希望的关联（SNP和CNV）。可从英国和美国GWAS进行大约4400例和4200个对照的Lllumina HumanHap 610芯片，使用Lllumina 317K芯片进行500例和300个对照，以及在澳大利亚使用520例Case和900个对照的汇总DNA分析，使用Lllumina 1M 1M Beadtype Chip进行了500例DNA分析。此外，英国GWAS在另外5,000例和5,000个对照中，基因分类近22,000个有前途的SNP。美国GWAS将在2009年10月对另外6,000例案例和6,000个控件进行询问。第二个目的是使用自定义的ISELECT LLLUMINA芯片复制发现，该发现在III期研究人群中的13,680个Beadtypes的其他大约3,500例和3,500个对照组的研究人群中没有任何阶段的阶段II或II阶段。总估计的三个阶段样本量将约为16,400例和17,100例对照，提供了出色的检测风险等位基因的功能，这对于项目2和3至关重要。第三个目的是检查所有合并的I阶段I和II阶段II和II阶段数据与卵巢癌存活有关的SNP和CNV的关联。对于目标四，我们将在阶段HI研究中设计并运行一个定制的ISELECT LLLUMINA芯片，该芯片为3,072个SNP，该研究人群的其他案例，可为其提供总体生存数据。总估计的三阶段生存样本量约为13,700例。我们将拟合顺序的遗传模型，以预测已知的临床预后因素的总体生存，并对其他主要组织学亚型（例如粘液和透明细胞）内的SNP关联进行探索性分析。