TWO HIT GENE MAPPING IN RENAL CELL CARCINOMA

描述(由申请人提供)：到目前为止发现的生殖系遗传变异通常只解释了包括肾细胞癌(RCC)在内的大多数癌症的部分预测遗传风险。剩余风险的一个组成部分可以通过个别非常罕见(或私人)的功能上随后的遗传变异来解释。这种遗传变异对肾癌易感性的影响尚不清楚。允许对这些变异进行不可知性、全基因组评估的策略可能需要非常重要的样本量才能获得足够的统计能力。除了昂贵的成本外，由于缺乏足够大的生物信息库，这种研究方法可能对罕见的癌症并不实用。不寻常的两次突变事件(一个突变在胚系中，第二个突变在同一个个体中)可能能够定位与肾癌易感性有关的基因。在特殊的IARC RCC生物信息库中，我们建议在发现和复制研究设计中使用这种“两次命中作图”的方法，以通过Knudson的两次命中模型来识别与肾癌遗传易感性相关的基因。

DESCRIPTION (provided by applicant): The germ-line genetic variants identified thus far generally explain only part of the predicted genetic risk for most cancers, including renal cell carcinoma (RCC). A component of the remaining risk may be explained by functionally consequent genetic variants that are individually very rare (or private). The contribution that thi spectrum of genetic variation makes to susceptibility to RCC remains unexplored. Strategies that allow for agnostic, genome-wide assessment of such variants are likely to require very important sample sizes for adequate statistical power. In addition to the large cost, such study approaches may not be practical for rare cancers due to the lack of sufficiently large bio-repositories. Unusual frequencies of "two-hit" mutation events (one mutation in the germ-line, and a second, somatic mutation in the same individual) may be able to map genes involved in RCC cancer susceptibility. Within the exceptional IARC RCC bio-repository, we propose to use this "two-hit mapping" approach in a discovery and replication study design to identify genes involved in genetic susceptibility to RCC acting via Knudson's two hit model.