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北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (3): 451-458. doi: 10.19723/j.issn.1671-167X.2019.03.012

• 论著 • 上一篇    下一篇

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

杨阳1,刘毅强2,王晓红3,季科1,李忠武2,白健4,杨爱蓉4,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△()   

  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, 1. 胃肠肿瘤中心
    2. 病理科
    3. 生物样本库, 北京 100142
    4. 和瑞基因科技有限公司,北京 102206
  • 收稿日期:2019-03-18 出版日期:2019-05-17 发布日期:2019-06-26
  • 作者简介:季加孚,教授、主任医师、博士生导师、国务院特殊津贴专家。现任北京大学肿瘤医院、北京大学临床肿瘤学院院长,北京市肿瘤防治研究所所长,教育部恶性肿瘤发病机制及转化重点实验室主任,北京大学肿瘤研究中心主任。
    兼任国际胃癌学会(International Gastric Cancer Association, IGCA)主席,中国抗癌协会副理事长,中国抗癌协会医院管理分会主任委员,中国医疗保健国际交流促进会副会长,中华医学会常务理事,中华医学会外科学分会常务委员兼秘书长,中国医师协会外科医师分会肿瘤外科医师委员会主任委员,约翰·霍普金斯大学医学院兼职教授,美国外科学院院士(Fellow of American College of Surgeons,FACS),英国皇家外科学院院士(Fellow of Royal Colleges of Surgeons, FRCS),亚洲外科学会(Asian Surgical Association,ASA)常务委员,中国人民政治协商会议第十三届全国委员会委员,中国民主同盟中央常务委员,中国民主同盟中央卫生与健康委员会主任。
    从事医教研一线工作36年,在领导实现胃癌外科手术共识、创新围手术期治疗模式、率先建立胃癌样本库、探索个体化治疗分子机制等方面做出重要贡献。以第一或通信作者在Nature Communications、Annals of Oncology、Clinical Cancer Research等杂志发表SCI论文127篇,主编国内首个SCI收录的肿瘤学期刊。以第一完成人获国家科技进步二等奖1项、省部级一等奖3项,获吴阶平-保罗·杨森医学药学奖及英国文化教育协会职业成就奖,是国家卫生健康委员会突出贡献专家、北京学者。
  • 基金资助:
    国家自然科学基金(81502643)

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

Yang YANG1,Yi-qiang LIU2,Xiao-hong WANG3,Ke JI1,Zhong-wu LI2,Jian BAI4,Ai-rong YANG4,Ying HU3,Hai-bo HAN3,Zi-yu LI1,Zhao-de BU1,Xiao-jiang WU1,Lian-hai ZHANG1△(),Jia-fu JI1△()   

  1. 1. Department of Gastrointestinal Cancer Center
    2. Department of Pathology
    3. Department of Biobank, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
    4. Berry Oncology Corporation, Beijing 102206, China
  • Received:2019-03-18 Online:2019-05-17 Published:2019-06-26
  • Supported by:
    Supported by the National Natural Science Foundation of China(81502643)

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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。

关键词: Epstein-Barr病毒感染, 胃肿瘤, 临床病理特征, 预后

Abstract: 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 metastasis and a good prognosis. It also has a distinct molecular background. The down-regulation of invasion/metastasis gene SALL4 and up-regulation of immune checkpoint gene PD-L1 are important molecular features.

Key words: Epstein-Barr virus infections, Stomach neoplasms, Clinicopathological features, Prognosis

中图分类号: 

  • R735.2

图1

原位杂交检测胃癌组织中的EBER表达"

表1

EBVaGC的临床病理特征"

Variables EBVaGC (n=163) EBVnGC (n=3 078) Statistics value P value
Gender, n χ2=10.783 0.001
Male 137 2 226
Female 26 852
Age/years, x?±s 55.9±10.8 59.7±11.1 t=16.959 <0.001
WHO classification, n χ2=399.138 <0.001
Adenocarcinoma 142 3 078
LELC 21 0
Lauren type, n χ2=16.547 <0.001
Intestinal-type 50 1 431
Diffuse-type 50 798
Mixed-type 63 849
Differentiation, n χ2=35.086 <0.001
Poorly 112 1 403
Moderately 51 1 581
Well 0 94
Location, n χ2=0.620 0.431
Cardia 34 814
Non-cardia 129 2 264
TNM stage, n χ2=6.797 0.079
Ⅰ 44 615
Ⅱ 32 688
Ⅲ 71 1 546
Ⅳ 16 229
T, n χ2=4.679 0.197
T1 31 499
T2 25 416
T3 62 1 437
T4 45 726
N, n χ2=4.772 0.029
Positive 92 1 996
Negative 71 1 082
M, n χ2=1.251 0.263
Positive 16 229
Negative 147 2 849
Vascular invasion, n χ2=7.775 0.005
Positive 62 1 586
Negative 91 1 460
Remnant GC or not, n χ2=8.204 0.004
Yes 7 44
No 156 3 034

表2

影响胃癌术后生存时间的单因素分析"

Variables HR (95%CI) P value
Age
18-50 1
50-90 1.156 (0.963-1.388) 0.121
Gender
Male 0.970 (0.816-1.155) 0.735
Female 1
EBER 0.040
Negative 1
Positive 0.627 (0.402-0.979)
WHO classification
Adenocarcinoma 1
LELC 0.049 (0.000-52.491) 0.398
Differentiation
Poor and moderate 1
Well 0.209 (0.078-0.558) 0.002
Location
Cardiac 1
Non-cardiac 1.065 (0.666-1.703) 0.792
TNM stage
Ⅰ 1
Ⅱ 4.402 (2.246-8.628) <0.001
Ⅲ 15.600 (8.334-29.203) <0.001
Ⅳ 18.541 (9.707-35.412) <0.001
Lymphatic metastatic
Negative 1
Positive 3.979 (3.159-5.011) <0.001

图2

EBVaGC和EBVnGC患者的生存曲线"

表3

影响胃癌术后生存时间的多因素分析"

Variables HR (95%CI) P value
EBER
Negative 1
Positive 0.609 (0.390-0.951) 0.029
TNM stage <0.001
Ⅰ 1
Ⅱ 2.904 (1.461-5.773) 0.002
Ⅲ 8.761 (4.557-16.844) <0.001
Ⅳ 10.816 (5.533-21.145) <0.001
Differentiation
Poor and moderate 1
Well 0.432 (0.161-1.163) 0.100
Lymph node metastasis
Negative 1
Positive 2.028 (1.577-2.606) <0.001

图3

TCGA数据库中胃癌数据集差异表达基因及其表达水平"

图4

不同SALL4和PD-L1表达的EBVaGC和EBVnGC患者生存曲线"

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ISSN 1671-167X
CN 11-4691/R
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