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，但几乎没有有效的治疗方法。Von Hippel-Lindau(VHL)基因突变与大多数散发性肾癌有关，并与VHL病的遗传综合征有关，在遗传综合征中，突变携带者有患肾细胞癌、神经系统血管母细胞瘤和嗜铬细胞瘤的风险。个体错义突变易导致这些肿瘤中的每一个的外显性。VHL蛋白(PVHL)参与了许多活动，其中最显著的是缺氧诱导因子HIF1-α和HIF2-α的氧依赖调控，它们转录调控着一大批缺氧反应基因。然而，pVHL的其他活性也是促进肿瘤的，因为仅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就有牵连，可能起到启动肿瘤的作用。促进侵袭性肾细胞癌发展的基因突变还不是很清楚，并且可能导致这种肿瘤对传统治疗方法的耐受性。了解VHL缺失的致癌活性的完整谱以及补充肾脏肿瘤进展的细胞事件是改进肾癌治疗的一个重要目标。这项建议概述了一种综合和平衡的方法来实现这一目标，方法是建立与VHL疾病全谱相关的VHL突变的体外和体内模型，并在小鼠模型系统中利用VHL疾病的强基因型：表型相关性。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启动肾癌变的过程，以及在VHL突变的背景下对可能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，可以并将在其中检查VHL诱导的致癌的许多方面，以便最终确定改进的肾癌患者的治疗方法。

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.