TWO HIT GENE MAPPING IN RENAL CELL CARCINOMA

描述（由申请人提供）：迄今为止鉴定的生殖系遗传变异通常只能解释大多数癌症（包括肾细胞癌（RCC））的部分预测遗传风险。剩余风险的一个组成部分可能是由功能上的遗传变异所解释的，这些变异个体非常罕见（或私人）。这种遗传变异谱对肾细胞癌易感性的贡献仍有待研究。允许对这些变异进行不可知的全基因组评估的策略可能需要非常重要的样本量以获得足够的统计功效。除了巨大的成本之外，由于缺乏足够大的生物储存库，这种研究方法对于罕见癌症可能不实用。不寻常的频率“两次击中”突变事件（一个突变在生殖系中，第二个突变在同一个体中）可能能够绘制与RCC癌症易感性有关的基因。在特殊的IARC RCC生物库中，我们建议在发现和复制研究设计中使用这种“两次击中映射”方法，以确定通过Knudson的两次击中模型作用的RCC遗传易感性相关基因。

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.