Pooled genome-wide analysis of kidney cancer risk

描述(申请人提供)：肾细胞癌(RCC)是美国第八种最常见的癌症，也是第十种最常见的癌症死亡形式，每年有超过34,000例病例和12,000例死亡。近几十年来，RCC的发病率急剧上升，其中一些最大的增长发生在中欧和美国的黑人人口中。除了吸烟、肥胖和高血压外，这种疾病的大部分病因仍有待确定。越来越多的证据表明，遗传因素影响肾癌的易感性，尽管这一假说尚未得到充分研究。我们最近完成了一项关于肾癌的全基因组关联研究，包括3,800个病例和8,500个对照。我们现在建议通过纳入来自一系列基于人群的病例对照和队列研究的另外3800个病例和4800个对照来扩展这项研究。通过NCI队列联盟倡议，促进了队列研究的纳入。除了其规模，我们的研究还将在几个方面具有独特性：(1)将收集大量的临床病理信息和病例的生存；(2)将针对疾病的发生和生存对遗传变异与肾癌之间的关系进行全基因组分析；(3)将建立至少2,000例病例的种系DNA和肿瘤DNA和RNA的综合生物库；(4)将获得新鲜肾组织和肿瘤组织的全基因组基因表达谱，以补充种系基因分型分析的结果。 与公共卫生相关：肾癌的发病率在过去几十年里一直在增加，在晚期确诊时，这种疾病的预后非常差(美国20%的病例)。除了吸烟、肥胖和高血压外，这种疾病的大部分病因仍有待确定。我们建议调查与肾癌发病和生存相关的遗传因素，观察整个基因组的遗传变异，并将其与肿瘤组织的基因表达分析相结合。

DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) is the 8th most common cancer in the US and the 10th most common form of cancer death, with over 34,000 cases and 12,000 deaths each year. A sharp increase in the incidence of RCC was observed in recent decades with some of the greatest increases happening in Central Europe and among the black population in the US. Apart from smoking, obesity and hypertension, much of the etiology of this disease remains to be identified. There is increasing evidence that genetic factors influence susceptibility to RCC, although this hypothesis has been understudied. We have recently completed a genome-wide association study (GWAS) of RCC comprising 3,800 cases and 8,500 controls. We now propose to extend this study by incorporating an additional 3,800 cases and 4,800 controls from a series of population based case-control and cohort studies. Inclusion of cohort studies has been facilitated via the NCI cohort consortium initiative. In addition to its size, our study will be unique in several ways: (1) extensive clinicopathological information and survival of cases will be collected; (2) genome-wide analyses for the association between genetic variants and RCC will be conducted for both disease onset and survival; (3) a comprehensive biorepository of germline DNA and tumor DNA and RNA on at least 2,000 cases will be developed; (4) whole-genome gene expression profiling on fresh renal tissue and tumor tissue will be obtained to complement results obtained from the germline genotyping analyses. PUBLIC HEALTH RELEVANCE: The incidence of kidney cancer has been increasing over the past decades and the disease has a very poor prognosis when diagnosed at an advanced stage (20% of the cases in the US). Apart from smoking, obesity and hypertension, much of the etiology of this disease remains to be identified. We propose to investigate genetic factors associated with kidney cancer onset and survival, looking at the genetic variants across the whole genome, and combining this with gene expression analysis of the tumor tissue.