Genomic Heterogeneity and the Small Renal Mass

项目概要和相关性 项目名称： 肾癌的发病率增加了三倍，由于小的（<4厘米），无症状的检测， 肿瘤的虽然目前的指南建议切除适合手术的患者，但这并不支持 高水平的证据。积极监测（密切影像学观察）对于小的肾肿瘤是一种有效的方法。 限制与不必要/过度治疗（包括围手术期）相关的伤害的替代方法 慢性肾脏疾病的发生和发展。当观察时，小肿瘤很少 显示快速增长和延迟干预始终是一种选择。一个重要的障碍存在于 通过主动监测，目前还没有可靠的方法来确定小肿瘤的生物学特性， 侵略性现在可以通过肾肿瘤活检评估基因组改变。然而 个体化治疗方法的主要障碍是对肿瘤异质性的担忧 从大型转移性肾脏肿瘤的研究中。肾小肿瘤的异质性程度 其临床相关性目前尚不清楚。利用癌症基因组图谱的现有数据，我们 将研究各种形式的肾癌的全球异质性程度及其相关性， 与肿瘤大小和预后有关。通过进行多区域测序，我们将研究区域性 常见驱动突变的差异以及新鲜、切除和 存档的肾肿瘤。这项研究将有助于了解肿瘤的临床意义， 异质性，并为涉及小肾的基于活检的生物标志物研究奠定基础 马萨诸塞州如果成功的话，这种方法可以限制过度治疗，节省患者不必要的治疗 这将有助于降低癌症的发病率，并减少这种癌症的经济负担（估计每年50亿美元）。 候选人： 我是一名专注于肾癌的泌尿外科医生。住院医师毕业后，我完成了泌尿肿瘤学 NCI提供了独特的肾癌临床培训。作为一个新的教员 作为耶鲁大学的一员，我希望能在遗传学，生物信息学， 和生物标志物开发。我会利用这段经历成为一名独立调查员 专注于肾癌的基因组生物标志物，并将其应用于不确定的临床情况， 哪些小肿瘤需要治疗我挑选了一位多才多艺的 导师团队我的主要导师，哈里特克鲁格博士专注于分子生物学， 晚期肾癌的生物标志物发现。其他导师，穆拉特古内尔博士和尤瓦尔克鲁格， 分别提供遗传学和生物信息学方面的专门知识。这个多元化的导师团队沿着 一个出色的教学培训计划将提高我独立进行翻译的能力 research.这项研究经验将与我的临床专业知识协同作用，为我提供 必要的工具，以调查目前的困境，在早期肾肿瘤。

PROJECT SUMMARY AND RELEVANCE Project: The incidence of kidney cancer has tripled due to increased detection of small (<4 cm), asymptomatic tumors. While current guidelines recommend resection in patients fit for surgery, this is not supported by high-level evidence. Active surveillance (close imaging observation) for small renal tumors is an alternative method to limit harms associated with unnecessary/overtreatment including perioperative complications and the development of chronic kidney disease. When observed, small tumors rarely demonstrate rapid growth and delayed intervention is always an option. A significant barrier exists in the adoption of active surveillance there are no reliable methods to determine a small tumors' biologic aggressiveness. Genomic alterations can now be assessed from a renal tumor biopsy. However a major obstacle to a personalized medicine approach are concerns raised over tumor heterogeneity from the study of large, metastatic kidney tumors. The extent of hetereogeneity in small renal tumors and its clinical relevance is currently unknown. Using existing data from the Cancer Genome Atlas, we will examine the extent of global heterogeneity in various forms of kidney cancer and its association with tumor size and prognosis. By performing multi-region sequencing, we will investigate regional differences in common driver mutations and the overall extent of heterogeneity in freshly, resected and archived renal tumors. This research will provide insight on the clinical significance of tumor heterogeneity and lay the foundation for biopsy based biomarker research involving the small renal mass. If successful, this approach could limit overtreatment and spare patients' unnecessary treatment morbidity as well as decreasing the economic burden of this cancer (an estimated $5 billion /year). Candidate: I am a urologic surgeon focused on kidney cancer. After residency, I completed a urologic oncology fellowship at the NCI, which provided unique clinical training in kidney cancer. As a new faculty member at Yale, I hope to obtain mentorship and didactic research training in genetics, bioinformatics, and biomarker development. I will harness this experience to become an independent investigator focused on genomic biomarkers in kidney cancer and apply it to uncertain clinical scenarios such which small tumors actually require treatment. I have selected an accomplished and multi-disciplinary mentorship team. My primary mentor, Dr. Harriet Kluger is focused on molecular biology and biomarker discovery in advanced kidney cancer. Other mentors, Drs. Murat Gunel and Yuval Kluger, provide expertise in genetics and bioinformatics, respectively. This diverse mentorship team along with an outstanding didactic training plan will enhance my ability to conduct independent translational research. This research experience will synergize with my clinical expertise to provide me with the necessary tools to investigate the current dilemmas in early stage renal tumors.