Genetic Events in the Development of Renal Cell Carcinoma

描述（申请人提供）：肾细胞癌是一种毁灭性的癌症，在美国每年影响36,600人，发病率稳步上升，但有效的治疗方法很少。von Hippel-Lindau （VHL）基因突变与大多数散发性肾癌和VHL疾病的遗传综合征有关，其中突变携带者有发生肾细胞癌、神经系统血管母细胞瘤和嗜铬细胞瘤的风险。个体错义突变可预测地倾向于这些肿瘤的外显率。VHL蛋白（pVHL）参与了许多活动，最值得注意的是缺氧诱导因子hif1 - α和hif2 - α的氧依赖性调节，这两个因子通过转录调控大量的缺氧反应基因。然而，pVHL的其他活性也促进肿瘤，因为与嗜铬细胞瘤相关的错义突变对缺氧反应基因的调节没有影响。然而，VHL突变在肾脏肿瘤发生的早期途径中有牵连，可能起肿瘤启动作用。增强侵袭性肾细胞癌发展的突变尚不清楚，并可能导致这种肿瘤对常规治疗的难治性。了解VHL丢失的致癌活动的全谱，以及补充肾脏肿瘤进展的细胞事件，是改善肾细胞癌治疗的一个重要目标。本提案概述了一种综合和平衡的方法，通过开发与VHL疾病全谱相关的VHL突变的体外和体内模型，并利用小鼠模型系统中VHL疾病的强基因型：表型相关性来实现这一目标。此外，我们提出了一种诱导肾小管中VHL的体细胞丢失的策略，以模拟VHL在肾癌发生中的起始，以及在VHL突变背景下推测的肾肿瘤“进展”途径的体细胞激活。这些研究将提供一个独特的模型系统，其中vhl诱导的癌变的许多方面可以并且将被检查，以便最终确定肾细胞癌患者的改进治疗方法。

DESCRIPTION (provided by applicant): Renal cell carcinoma is a devastating cancer affecting 36,600 individuals per year in the US and rising steadily in incidence, but with few effective treatments. Mutations in the von Hippel-Lindau (VHL) gene have been associated with the majority of sporadic cancers of the kidney, and with the hereditary syndrome of VHL disease in which mutational carriers are at risk for development of renal cell carcinoma, as well as hemangioblastoma of the nervous system, and pheochromocytoma. Individual missense mutations predispose predictably to the penetrance of each of these tumors. VHL protein (pVHL) has been implicated in many activities, most notably the oxygen dependent regulation of the hypoxia inducible factors HIF1-alpha and HIF2-alpha which trancriptionally regulation a large cohort of hypoxia response genes. However, other activities of pVHL are also tumor-promoting, as missense mutations associated with exclusively pheochromocytoma have no effect on regulation of hypoxia response genes. VHL mutation, however, is implicated early in the pathway of tumorigenesis of the kidney, likely playing a tumor-initiating role. The mutations which augment the development of invasive renal cell carcinoma are not well-understood, and may contribute to the refractoriness of this tumor to conventional therapies. Understanding the complete spectrum of carcinogenic activities of VHL loss as well as the cellular events which supplement tumor progression in the kidney is an essential goal in a mission to improve treatments for renal cell carcinoma. This proposal outlines an integrated and balanced approach to meeting this goal by developing in vitro and in vivo models of VHL mutations associated with the complete spectrum of VHL disease, and exploiting the strong genotype:phenotype correlation of VHL disease in a mouse model system. Additionally, we propose a strategy to induce somatic loss of VHL in the kidney tubule to model VHL initiation of renal carcinogenesis, as well as somatic activation of putative renal tumor "progression" pathways in a background of VHL mutation. These investigations will provide a unique model system in which many aspects of VHL-induced carcinogenesis can and will be examined in order to ultimately identify improved treatments for patients with renal cell carcinoma.