单中心大样本Epstein-Barr病毒相关性胃癌亚型的临床病理及分子特征分析  

Clinicopathological and molecular characteristics of Epstein-Barr virus associated gastric cancer: a single center large sample case investigation

作　　者：杨阳 刘毅强[2] 王晓红[3] 季科[1] 李忠武[2] 白健 杨爱蓉 胡颖[3] 韩海勃[3] 李子禹[1] 步召德[1] 吴晓江[1] 张连海[1] 季加孚[1,5,6,7,8,9,10,11,12,13,14,15,16,17,18] YANG Yang;LIU Yi-qiang;WANG Xiao-hong;JI Ke;LI Zhong-wu;BAI Jian;YANG Ai-rong;HU Ying;HAN Hai-bo;LI Zi-yu;BU Zhao-de;WU Xiao-jiang;ZHANG Lian-hai;JI Jia-fu(Department of Gastrointestinal Cancer Center,Key Laboratory of Carcinogenesis and Translational Research,Ministry of Education,Laboratory of Genetics,Peking University Cancer Hospital & Institute,Beijing 100142,China;Fellow of American College of Surgeons,FACS;Fellow of Royal Colleges of Surgeons, FRCS;Asian Surgical Association,ASA;Department of Pathology,Key Laboratory of Carcinogenesis and Translational Research,Ministry of Education,Laboratory of Genetics,Peking University Cancer Hospital & Institute,Beijing 100142,China;Department of Biobank,Key Laboratory of Carcinogenesis and Translational Research,Ministry of Education,Laboratory of Genetics,Peking University Cancer Hospital & Institute,Beijing 100142,China;Berry Oncology Corporation,Beijing 102206,China;International Gastric Cancer Association, IGCA)

机构地区：[1]北京大学肿瘤医院暨北京市肿瘤防治研究所,恶性肿瘤发病机制及转化研究教育部重点实验室,胃肠肿瘤中心,北京100142 [10]中华医学会外科学分会 [11]中国医师协会外科医师分会肿瘤外科医师委员会 [12]约翰·霍普金斯大学医学院 [13]美国外科学院 [14]英国皇家外科学院 [15]亚洲外科学会 [16]中国人民政治协商会议第十三届全国委员会 [17]中国民主同盟 [18]中国民主同盟中央卫生与健康委员会 [2]北京大学肿瘤医院暨北京市肿瘤防治研究所,恶性肿瘤发病机制及转化研究教育部重点实验室,病理科,北京100142 [3]北京大学肿瘤医院暨北京市肿瘤防治研究所,恶性肿瘤发病机制及转化研究教育部重点实验室,生物样本库,北京100142 [4]和瑞基因科技有限公司,北京102206 [5]国际胃癌学会 [6]中国抗癌协会 [7]中国抗癌协会医院管理分会 [8]中国医疗保健国际交流促进会 [9]中华医学会

出　　处：《北京大学学报（医学版）》2019年第3期451-458,共8页Journal of Peking University:Health Sciences

基　　金：国家自然科学基金(81502643)~~

摘　　要：目的: Epstein-Barr病毒相关性胃癌(Epstein-Barr virus associated gastric cancer, EBVaGC)与常见胃癌(非Epstein-Barr病毒相关性胃癌,Epstein-Barr virus non-associated gastric cancer, EBVnGC)不同,具有独特的临床病理特征,本研究采用单中心大样本探讨中国EBVaGC的临床病理及分子特征。方法:回顾分析2003—2018年北京大学肿瘤医院EBVaGC与EBVnGC两组患者的临床病理特征和预后。分析公共数据库胃癌数据集,筛选显著差异表达基因,并在本组病例中验证重要基因的表达及其与预后的相关性。结果: 3 241例胃癌患者纳入研究,EBVaGC为163例,占总数的5.0%。与EBVnGC相比,EBVaGC男性常见,平均年龄低,多见于残胃癌,常为低分化腺癌、Lauren混合型,较少出现淋巴结转移,EBVaGC患者的5年生存率为63.2%,优于EBVnGC的59.6%( P <0.05)。为挖掘EBVaGC的分子特征,对癌症基因组图谱(The Cancer Genome Atlas, TCGA)胃癌数据集( n =240)进行分析,筛选到7 404个显著差异表达基因,涉及细胞增殖、凋亡、侵袭转移等功能,其中侵袭转移相关基因 SALL4 下调、免疫检查点相关基因 PD-L1 上调是EBVaGC重要的分子特征。大样本验证显示,SALL4在EBVaGC中多为阴性(1/92,1.1%,低于EBVnGC的303/1 727,17.5%),PD-L1在EBVaGC中多为阳性(81/110,73.6%,高于EBVnGC的649/2 350,27.6%),SALL4阴性和PD-L1阳性患者的预后较好。结论: EBVaGC作为独特的胃癌亚型,较少出现转移且预后良好,该亚型具有特征性分子背景,其中侵袭转移相关基因 SALL4 的下调以及免疫检查点相关基因 PD-L1 的上调是重要的分子特征。Objective: Epstein-Barr virus associated gastric cancer (EBVaGC) is different from the traditional gastric cancer (Epstein-Barr virus non-associated gastric cancer, EBVnGC), and has unique clinicopathological features. This study investigated the largest single center cancer series so as to establish the clinicopathological and molecular characteristics of EBVaGC in China. Methods: A retrospective analysis was conducted on EBVaGC and EBVnGC patients diagnosed at Peking University Cancer Hospital from 2003 to 2018 by comparing their clinicopathological features and prognosis. The gastric cancer (GC) dataset of public database was analyzed to obtain differentially expressed genes. The expression of important genes and their association with prognosis of GC were verified in GC tissues from our hospital. Results: In this study, 3 241 GC patients were included, and a total of 163 EBVaGC (5.0%) patients were identified. Compared with EBVnGC, EBVaGC was higher in male and younger patients, and positively associated with remnant GC, poorly differentiated adenocarcinoma, and mixed type GC. EBVaGC was inversely related to lymph node metastasis. The 5-year survival rate of EBVnGC and EBVaGC was 59.6% and 63.2% respectively ( P <0.05). In order to explore molecular features of EBVaGC, the Cancer Genome Atlas (TCGA) dataset was analyzed ( n =240), and 7 404 significant differentially expressed genes were obtained, involving cell proliferation, apoptosis, invasion and metastasis. The down-regulated invasion/metastasis gene SALL4 and the up-regulated immune checkpoint gene PD-L1 were important molecular features of EBVaGC. Validation of these two genes in large GC series showed that the majority of the EBVaGC was SALL4 negative (1/92, 1. 1 %, lower than EBVnGC, 303/1 727, 17.5%), and that PD-L1 was mostly positive in EBVaGC (81/110, 73.6%, higher than EBVnGC, 649/2 350, 27.6%). GC patients with SALL4 negative and PD-L1 positive were often associated with better prognosis. Conclusion: EBVaGC is a unique subtype of GC with less m

关 键 词：EPSTEIN-BARR病毒感染 胃肿瘤 临床病理特征 预后 

分 类 号：R735.2[医药卫生—肿瘤]