上皮性卵巢癌发病是一个多基因突变的复杂过程。DNA聚合酶epsilon(Pol ε)由催化亚基POLE1和另外3个调控亚基组成，在细胞内行使DNA复制及错配修复功能，其功能异常能诱发肿瘤。近期，我们首次在上皮性卵巢癌中发现POLE1高频突变，进化保守性分析结果表明其为有害突变，可能影响Polε的DNA错配修复功能。然而对于POLE1突变在卵巢癌发病中的作用，有3个重要问题尚不清楚：该突变能否真正促进卵巢癌发病？该突变能否增加患者肿瘤基因组突变率？该突变与其中的哪些驱动基因突变协同作用，促进卵巢癌发病？本项目拟继续检测上皮性卵巢癌患者的POLE1突变，并明确其致癌性；全基因组测序找出POLE1突变患者肿瘤基因组的体细胞突变，甄别其中的驱动突变并证实其促癌性，以验证其能否与POLE1突变协同作用促进卵巢癌发病。研究结果将明确POLE1突变的促癌性及分子机制、为患者分子靶向治疗提供理论依据。

The pathogenesis of epithelial ovarian carcinoma (EOC) is a complex process with mutations in multiple genes. DNA polymerase epsilon (Pol ε) is composed of a catalytic subunit POLE1 and three other regulatory subunits, its primary function involves the processes of DNA replication and DNA mismatch repair, dysfunction of this polymerase would promote the development of tumors. Recently, we identified a high frequency of POLE1 mutation in our EOC samples for the first time, the evolutionary conservation analysis suggested that POLE1 mutation was a damaging mutation and might cause the dysfunction of DNA mismatch repair in Pol ε. However, regarding the roles of the POLE1 mutation played in the carcinogenesis of EOC, three crucial questions remain to be answered, that is, whether POLE1 mutation could promote the carcinogenesis of EOC? Whether POLE1 mutation would cause DNA mutation rate increase in the cancer genome of the affected samples? Which driver mutations would play synergetic roles with POLE1 mutation in the development of EOC? In the current project, we will perform the following assays to answer these questions: we will continue to perform the mutational screen of the POLE1 gene in Chinese patients with EOC, and confirm the potential tumor-promoting roles of POLE1 mutation via functional assays; then we will search for the global somatic mutations in the cancer genomes of the POLE1-mutated EOC patients via whole genome sequencing, then select the potential driver mutations and confirm their potential tumor-promoting roles, to test whether these mutations will play synergetic roles with POLE1 mutations in the development of EOC. These results will help us to clarify the roles and molecular mechanisms of POLE1 mutation in the carcinogenesis of EOC, and provide theoretical bases for the molecular target therapy for the patients with POLE1 mutation.