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目的:对一个Ⅱ型糖尿病(T2DM)合并恶性肿瘤复杂家系进行基因变异分析，筛选其候选致病/易感基因。方法:用全外显子组测序(WES)技术对T2DM合并恶性肿瘤复杂家系的11名成员进行DNA测序，用生物信息学方法筛选候选致病/易感突变，并用Sanger测序对候选突变进行验证。结果:该家系共21人，其中11人诊断为T2DM，7人诊断为乳腺癌、胃癌、胰腺癌或脑瘤。对11名家系成员(7人诊断为T2DM，两人诊断为乳腺癌)进行了WES测序分析，筛选出6个候选糖尿病相关突变，其中功能丢失型(TOF)突变1个为瞬时受体电位阳离子M亚家族成员1(TRPM1) c．G4240T p．E1414X；非LOF突变5个，涉及腺苷酸激酶7(AK7)、CROCC、溶质载体家族15成员1(SLC15A1)、丝氨酸羟甲基转移酶2(SHMT2)、Teashirt锌指同源异型盒2(TSHZ2)基因。同时还筛选得到4个肿瘤相关遗传位点(rs3184504、rs1053338、rs11894115和rs11552449)。结论:TRPM1 c．G4240T变异可能是导致该家系糖尿病合并肿瘤发生的关键候选变异；而rs3184504、rs1053338、rs11894115和rs11552449遗传位点可能为该家系乳腺癌易感性位点。“,”Objective:To screen potential pathologic variants in a complicated family affected with diabetes mellitus and cancer.Methods:Whole exome sequencing (WES) was used to scan the whole exome of 11 members of a family affected with type 2 diabetes mellitus (T2DM) and cancer. Suspected pathologic variants or susceptibility risk loci were predicted using bioinformatics tools and further verified by Sanger sequencing.Results:The collected family included 21 members. Of them, a total of 11 persons were diagnosed with T2DM, and 7 with breast cancer, gastric cancer, pancreatic cancer or brain tumor. WES was performed on 11 cases, including 7 patients of T2DM and 2 patients of breast cancer. A total of 6 candidate diabetes-related variants were identified, including one lost-of-function (LOF) mutation (TRPM1 c. G4240T p. E1414X) and five non-LOF variants located in AK7, CROCC, SLC15A1, SHMT2 and TSHZ2. In addition, 4 cancer-related variants (rs3184504, rs1053338, rs11894115 and rs11552449) were identified.Conclusion:The variant of TRPM1 c. G4240T appears to be the key variant underling T2DM and cancers in this family, and 4 variants, including rs3184504, rs1053338, rs11894115 and rs11552449, are potential genetic susceptibility risk loci for breast cancer.