肾透明细胞癌中SETD2基因突变介导DNA错配修复系统功能受损的机制研究

项目名称： 肾透明细胞癌中SETD2基因突变介导DNA错配修复系统功能受损的机制研究

项目编号： No.81502189

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 冯陈陈

作者单位： 复旦大学

项目金额： 18万元

中文摘要： 肾透明细胞癌(ccRCC)的发生发展与基因突变关系密切。近期发现SETD2基因在ccRCC中存在高频突变且与预后相关。我们前期发现SETD2突变可激活PI3K/AKT通路从而显著抑制DNA错配修复(MMR)系统中重要元件PMS2表达，而ccRCC组织中SETD2与另一MMR基因MLH1在3p上常发生共缺失，提示SETD2突变/缺失可能通过MLH1及PI3K/AKT/PMS2双重途径损害MMR功能。本项目将通过整合大型数据库数据、ccRCC组织学样本以及分子生物学实验全面分析MMR在SETD2突变型肾癌中的稳定性，首次尝试从MMR功能受损导致遗传不稳定的角度来阐述SETD2突变在肾癌中促进肿瘤增殖及侵袭的分子机理，揭示外源性提高MMR蛋白水平在增加SETD2突变型肾癌对PI3Kβ抑制剂敏感性中的作用和机制，为肾癌的发病机制和治疗提供新思路和新策略。

中文关键词： 肾肿瘤；错配修复；基因突变

英文摘要： Clear-cell renal cell carcinoma (ccRCC) can be distinguished by underlying gene mutations among which SETD2 mutation is recently found to be associated with high mutant frequency and prognosis. We previously found that SETD2 mutated ccRCC exhibited increased PI3K/AKT activity and resultant decrease of critical mismatch repair (MMR) machinery element PMS2. Homozygous loss of SETD2 and another MMR gene MLH1 on 3p also occurred at high odds ratio in ccRCC. These results indicate that SETD2 mutation could impair MMR function in ccRCC. We aim to integrate massive genomic database, collect ccRCC samples and perform molecular biological studies to assess the stability of MMR in different SETD2 status. We speculate that impairment of MMR causes hereditary instability and maintains tumour growth and invasiveness in SETD2-mutated ccRCC. Also, we surmise that addition of MMR proteins could enhance the efficacy of PI3Kβ inhibitor in SETD2-mutated ccRCC, holding promise to the development of targeted therapy in ccRCC with specific genomic background.

英文关键词： Renal cell carcinoma;Mismatch repair;Gene mutation