一个Ⅱ型糖尿病合并恶性肿瘤发生家系的基因变异分析

Mutation analyses of a complicated family affected with diabetes mellitus and cancer

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.