胃癌组织PBRM1基因缺失/突变的临床病理意义和分子改变

Abnormality of PBRM1 gene deletion/mutation in gastric cancer tissue and its related clinicopathological significance and molecular changes

目的探讨胃癌布罗莫结构域1(PBRM1)基因改变及其相关的临床病理特征和分子改变。方法应用cBioPortal(258例)及LinkedOmics(393例)数据集统计分析PBRM1基因缺失/突变与胃癌临床病理参数、预后及分子改变的关系。收集2016-01-01-2016-12-31南京医科大学附属无锡人民医院233例胃癌组织通过免疫组化法进行初步统计验证。结果公开数据库显示,胃癌中PBRM1缺失/突变占9.30%(24/258),其PBRM1 mRNA表达显著减少,LogFC=-0.538,P<0.001。PBRM1缺失/突变与富集分析的拷贝数(χ^(2)=11.063)及甲基化(χ^(2)=24.056)、CpG岛甲基化表型(CIMP)类别(χ^(2)=23.635),MLH1沉默(χ^(2)=22.437)、微卫星稳定(MSI)状态(χ^(2)=35.696)、分子亚型(χ^(2)=38.125)、ARID1A突变(χ^(2)=23.689)、超突变(χ^(2)=31.404)以及PIK3CA突变(χ^(2)=29.917)有显著关联性,均P<0.01.PBRM1 mRNA表达与其启动子甲基化呈显著负相关,Pearson相关系数=-0.359,P<0.001。PBRM1突变与免疫抑制分子细胞程序性死亡配体1(PDL1;CD274)及细胞毒性T淋巴细胞相关蛋白4(CTLA4)mRNA高表达显著相关,LogFC分别为0.898和0.683,均P<0.001。PBRM1基因突变患者预后较好,χ^(2)=-0.501,P=0.231。病例收集验证部分显示,233例中34例(14.6%)PBRM1表达缺失,并与错配修复(MMR)蛋白丢失显著相关,χ^(2)=8.592,P=0.003;与p53异常表达显著负相关,χ^(2)=-4.414,P=0.036。PBRM1表达缺失患者预后显著较好,χ^(2)=3.958,P=0.047。结论PBRM1基因异常在-部分胃癌亚群中可能具有重要的致癌作用及预后意义,PBRM1基因异常检测及相关机制的应用可能成为胃癌的新型预后标志物及治疗策略。

Objective To explore the abnormality of gastric cancer(GC)PBRM1 gene and its related clinical pathological features and molecular changes.Methods The cBioPortal(258 cases)and LinkedOrriics(393 cases)data sets were used to analyze the relationship between PBRM1 gene deletion/mutation and clinical pathological parameters,prognosis and molecular changes of GC.A total of 233 cases of GC from 2016-01-01 to 2016-12-31 were collected for preliminary statistical verification by immunohistochemistry.Results The public database showed that 9.30%(24/258)of PBRM1 deletion/mutation were detected and its PBRM1 mRNA expression was significantly reduced in GC(LogFC=-0.538,P<0.001).PBRM1 deletion/mutation was significantly associated with copy number(χ^(2)=11.063)and methylation(χ^(2)=24.056)of enrichment analysis,CpG island methylator phenotype(CIMP)category(χ^(2)=23.635),MLH1 silencing(χ^(2)=22.437),microsatellite instability(MSI)status(χ^(2)=35.696),molecular subtype(χ^(2)=38.125),ARID1A mutation(χ^(2)=23.689),hypermutation(χ^(2)=31.404)and PIK3CA mutation(χ^(2)=29.917,P<O.01).PBRM1 mRNA.expres­sion was significantly negatively correlated with promoter methylation(Pearson correlation=-0.359,PV0.001).PBRM1 mutation was sigrdficantly associated with high expression of immunosuppressive molecule PDL1(CD274)and CTLA4 mRNA(LogFC were 0.8977 and 0.6828 respectively,P values were<0.001).Patients with PBRM1 gene mu­tation had a better prognosis(χ^(2)=-0.501,P=0.231).Case verification showed that 34 cases(14.6%)showed loss of PBRM1 expression,which was significantly related to mismatch repair(MMR)protein loss(χ^(2)=8.592,P=0.003)and was significantly negatively related to abnormal p53 expression(χ^(2)=-4.414,P=0.036).The prognosis of patients with PBRM1 expression loss was significantly better(χ^(2)=3.958,P=0.047).Conclusion PBRM1 gene abnormality may have important carcinogenic effects and prognostic significance in a GC subgroup,and some characteristic molecular changes are associated with it,which can be used in the diagnosis and treatment of GC,such as being used as a predictive marker for immunotherapy and developing synthetic lethal-related therapies.