血清甲胎蛋白升高伴肠母细胞分化胃腺癌的分子特征分析  

Clinicopathological analysis of gastric adenocarcinoma with elevated serum alpha-fetoprotein and enteroblastic differentiation

作　　者：昝丽坤[1] 申璐璐 张鑫[2] 高宁[1] 田宝国 耿小鑫 彭潇 李佳芠 步鹏[1] 赵国海 Zan Likun;Shen Lulu;Zhang Xin;Gao Ning;Tian Baoguo;Geng Xiaoxin;Peng Xiao;Li Jiawen;Bu Peng;Zhao Guohai(Department of Pathology,Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated Cancer Hospital,Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University,Taiyuan 030013,China;Department of Colorectal Surgery,Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated Cancer Hospital,Chinese Academy of Medical Sciences/Cancer Hospital Affiliated Shanxi Medical University,Taiyuan 030013,China;Department of Medical Laboratory,Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated Cancer Hospital,Chinese Academy of Medical Sciences/Cancer Hospital Affiliated Shanxi Medical University,Taiyuan 030013,China;School of Basic Medicine,Shanxi Medical University,Taiyuan 030001,China)

机构地区：[1]山西省肿瘤医院/中国医学科学院肿瘤医院山西医院/山西医科大学附属肿瘤医院病理科,太原030013 [2]山西省肿瘤医院/中国医学科学院肿瘤医院山西医院/山西医科大学附属肿瘤医院结直肠外科,太原030013 [3]山西省肿瘤医院/中国医学科学院肿瘤医院山西医院/山西医科大学附属肿瘤医院医学检验部,太原030013 [4]山西医科大学基础医学院,太原030001

出　　处：《中华肿瘤杂志》2024年第7期686-695,共10页Chinese Journal of Oncology

基　　金：山西省科技厅基础研究项目(201801D21308,202303021211232);山西省留学回国人员科技活动择优资助项目(20191176);山西省卫生健康委员会科研项目(2014047);国家肿瘤区域医疗中心科教培育基金第一批资助项目山西省肿瘤医院硕导伴飞基金(SD2023018)。

摘　　要：目的探讨血清甲胎蛋白(AFP)升高伴肠母细胞分化胃腺癌(GAED)患者的免疫表型和分子生物学特征。方法收集2018—2020年山西省肿瘤医院收治的13例血清AFP升高且伴有GAED患者的临床病理资料,应用免疫组织化学(IHC)及二代测序方法对13例血清AFP升高伴GAED患者的病理组织进行免疫标志物和分子生物学特征分析,生存分析采用Kaplan-Meier法和Log rank检验。结果13例GAED患者中,男12例,女1例,年龄41~70岁,中位年龄64岁,病灶位置以胃窦部(5例)、胃体部(4例)为主。IHC显示可表达瘤胚胎蛋白(AFP、SALL4、GPC3)、肠上皮分化蛋白(CDX-2、CD10)和一些原始肠上皮表型标志物(OCT3/4、Claudin6),联合应用多种标志物诊断可降低漏诊率。13例患者中,12例存在至少1个基因突变(1个基因突变:1例,2~5个基因突变:3例,6~15个基因突变:8例),1例未检测到突变。突变频率最高的基因是TP53(10例),其他突变基因包括EPHB1(3例)、ATRX(2例)、EPHA5(2例)、GATA3(2例)、LRP1B(2例)和MAP2K4(2例)。13例患者中3例存在基因结构变异,分别为C14orf177-GNAS、AIM1-FGFR3、EPHA6-ROS1基因重排。13例患者均存在拷贝数变异,11例患者存在2个以上基因的拷贝数变异。常见的扩增基因为IRS2(5例)、PTEN(5例)、GNAS(4例)、CCNE1(3例)、CEBPA(3例)、PCK1(3例)、ERBB2(2例),常见的缺失基因为SOX2(5例)、MYC(5例)。13例患者中,死亡4例,死亡患者中有2例出现肝转移;无病生存患者4例,5例患者病情进展,其中3例出现腹腔转移,2例出现肝转移。血清AFP升高伴GAED患者3年生存率为65.9%,3年无进展生存率为30.7%。基因LRP1B点突变与预后不良有关(P<0.001)。行免疫治疗较单纯化疗的患者预后无明显改善(P=0.595),但进行术后化疗或术后化疗加免疫治疗较只进行手术患者预后好(均P<0.05)。结论血清AFP升高伴GAED是一种具有高度侵袭性的肿瘤,有独特的分子特征,往往同时伴有多个分子事件,TP53突变�Objective To investigate the immunophenotypic and molecular biological characteristics of patients with elevated serum alpha-fetoprotein(AFP)and enteroblastic differentiated gastric adenocarcinoma(GAED).Methods The clinicopathological data of 13 patients with elevated serum AFP and GAED admitted to Shanxi Cancer Hospital from 2018 to 2020 were collected.Immunohistochemistry(IHC)and next-generation sequencing(NGS)were used to analyze the immune markers and molecular biological characteristics of the pathological tissues of the patients.Kaplan-Meier method and log rank test were used for survival analysis.Results Among the 13 patients with GAED,12 were male and 1 was female,aged 41-70 years,with a median age of 64 years.The lesions were mainly located in the gastric antrum(5 cases)and gastric body(4 cases).IHC results showed that the tumor embryonic protein(AFP,SALL4,GPC3),intestinal epithelial differentiation protein(CDX-2,CD10),and some original intestinal epithelial phenotype markers(OCT3/4,Claudin6)were expressed in the tumor tissues.Combined application of multiple markers can reduce the rate of missed diagnosis.Among the 13 patients,12 had at least one mutation(1 mutation:1 case,2-5 mutations:3 cases,6-15 mutations:8 cases),and 1 case was not detected.The gene with the highest mutation frequency was TP53(10 cases),and other mutant genes included EPHB1(3 cases),ATRX(2 cases),EPHA5(2 cases),GATA3(2 cases),LRP1B(2 cases)and MAP2K4(2 cases)were also detected.Three of the 13 patients had structural variations,which were C14orf177-GNAS,AIM1-FGFR3,and EPHA6-ROS1 gene rearrangements.All 13 patients had copy number variation,and 11 patients had copy number variation of more than 2 genes.The common amplification genes were IRS2(5 cases),PTEN(5 cases),GNAS(4 cases),CCNE1(3 cases),CEBPA(3 cases),PCK1(3 cases)and ERBB2(2 cases).The common deletion genes were SOX2(5 cases)and MYC(5 cases).Among the 13 patients,4 died,and 2 of the dead patients had liver metastasis.There were 4 patients with disease-free survival and 5 pati

关 键 词：胃肿瘤 肠母细胞分化 病理特征 分子特征 治疗 预后 

分 类 号：R735.2[医药卫生—肿瘤]