LETM 2基因在胃癌中的表达及其对胃癌腹膜转移预测和预后的意义

Expression of LETM2 Gene in Gastric Cancer and its Significance for Prognosis and Peritoneal Metastasis Prediction

目的探讨LETM2免疫组织化学染色(IHC)对胃癌腹膜隐匿转移灶检测及预后的预测价值。方法通过加权基因共表达网络分析(WGCNA)在GSE62254数据集中获得胃癌腹膜转移关键模块,基于GEO(GSE62254和GSE84437)和TCGA数据集的单因素COX回归分析筛选胃癌预后相关的基因,取关键模块的预后相关基因进行临床样品IHC分析。结果深绿色模块为腹膜转移相关的关键模块,以关键模块与3个数据集预后相关基因的交集之一LETM 2作为候选基因。IHC分析结果评分显示,LETM2在弥漫型胃腺癌(9.29±0.17)和腹膜转移灶(9.85±0.47)中表达最高,在淋巴结(3.99±0.21)和肝转移灶(5.13±0.72)中表达较高,在邻近正常胃黏膜上皮(2.95±0.13)和肠型胃腺癌(2.84±0.25)中低表达。LETM2在原发性肿瘤中高表达是胃癌的不良预后指标(log Rank P=0.02),与腹膜转移(P=0.002)、Lauren分型(P<0.001)和pStage(P=0.003)呈正相关。ROC曲线分析显示,胃癌原发灶LETM2 IHC评分对胃癌腹膜转移预测的最佳截止值为6.5,曲线下面积为0.626(95%CI:0.519~0.733),灵敏度为90.0%,特异度为43.0%;腹水细胞沉渣蜡块LETM2 IHC检测腹膜转移灶的灵敏度为75.0%,特异度为83.3%。结论LETM2高表达是胃癌腹膜转移和预后不良的潜在预测标记物。

Objective To explore the predictive value of LETM2 immunohistochemical staining(IHC)for the detection of peritoneal metastasis and prognosis of gastric cancer.Methods Weighted gene co-expression network analysis(WGCNA)was used to identify key modules correlated with peritoneal metastasis in the GSE62254 datasets.Prognosis-related genes across GSE84437,GSE62254 and TCGA datasets were identified based on univariate COX regression.Intersected genes of both gene groups were identified to be further validated in clinical samples by IHC.Results Darkgreen module was positively correlated with peritoneal metastasis,LETM2 of the darkgreen module associated with prognosis in the GSE62254,GSE84437 and TCGA datasets was recognized as candidate key gene.IHC confirmed that LETM2 expression was higher in diffuse type gastric cancer(9.29±0.17)and peritoneal metastatic loci(9.85±0.47),moderate in lymph node and liver metastatic loci(3.99±0.21 and 5.13±0.72 respectively),and low in adjacent normal gastric epithelium and intestinal gastric adenocarcinoma(2.95±0.13 and 2.84±0.25 respectively).High LETM2 expression in primary tumor was positively correlated with peritoneal metastasis(P=0.002),diffuse type gastric cancer of Lauren classification(P<0.001)and advanced pStage(P=0.003).The optimal cut off value of immunohistochemical score for peritoneal metastasis was 6.5 based on ROC curve analysis.The area under ROC curve was 0.626(95%CI:0.519-0.733)with sensitivity reaching 90.0%and specificity reaching 43.0%.LETM2 immunohistochemistry in sections from ascites sediments can detect tumor cells with true positive rate(sensitivity)at 75%and true negative rate(specificity)at 83.3%.Conclusion High LETM2 expression in gastric cancer is a potentialy predictive marker for peritoneal metastasis and poor prognosis.