DNA损伤修复的缺陷在肿瘤发生中有重要作用。项目组发现一类既有淋巴瘤又有其它类型肿瘤的家系，即淋巴瘤多肿瘤家系。对其中一个家系的研究揭示错配修复基因的胚系突变不仅导致了林奇综合征，还参与到套细胞淋巴瘤的发生。为了明确DNA修复基因胚系突变在家系多肿瘤发生与淋巴瘤演化中的作用，以及对家系淋巴瘤预后的影响，我们拟对多肿瘤家系展开外显子组测序分析，确定家系内患者共有胚系突变和淋巴瘤患者特有胚系突变，通过突变体功能实验和家系肿瘤样本体细胞突变分析确定致病胚系突变，评估肿瘤家族史和胚系突变对淋巴瘤患者疗效与生存的影响，建立家系淋巴瘤PDX模型初步筛选靶向药物。该研究不仅对阐明肿瘤发生机制有重要意义；对携带致病胚系突变的患者其长期治疗方案的制定都有指导；此外，明确致病胚系突变也是肿瘤分子诊断、早期筛查、遗传咨询、靶向药物研发，即肿瘤精准医疗的重要基础。

Defects of DNA damage repair play a key role in tumorigenesis. We find some families with both lymphoma and cancers, i.e. lymphoma-cancer family. In one family, the germline mutation of a mismatch repair gene not only causes Lynch syndrome, but also participates in the development of mantle cell lymphoma. We aim to understand the role of germline defects of DNA repair in tumorigenesis including lymphomagenesis, and in prognosis of lymphoma. And we propose to perform exome analyses of the lymphoma-cancer families, and identify germline mutations shared by all affected family members and specific mutations for lymphoma. Germline mutations predisposing to cancers or lymphoma will be validated through functional studies and analyses of somatic mutations in tumors. The influence of family history of tumor and germline mutations on the response rate to therapy and survival in lymphoma patients will be evaluated. Furthermore, PDX models of lymphoma will be established for the screening of targeted therapies. This study is not only important for our understanding of tumorigenesis, but also meaningful for the long term therapy of tumor patients carrying pathogenic germline mutations. Furthermore, germline mutations are fundamental for molecular diagnosis, early screening, genetic counseling and the development of targeted therapies, or precision medicine of tumor.