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Journal of Peking University(Health Sciences) ›› 2019, Vol. 51 ›› Issue (3): 451-458. doi: 10.19723/j.issn.1671-167X.2019.03.012

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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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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

CLC Number: 

  • R735.2

Figure 1

EBER expression in human primary gastric cancer by in situ hybridization A, EBER negative (×200); B, EBER positive (×200); C, LELC exhibits “lace-like” pattern by HE staining (×40). EBER, Epstein-Barr virus encoded small RNA; LELC, lymphoepithelioma-like carcinoma."

Table 1

The clinicopathological features of EBVaGC"

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

Table 2

Univariate Cox regression analysis of prognostic factors for gastric cancer patients"

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

Figure 2

Kaplan-Meier curves of EBVaGC and EBVnGC A, Kaplan-Meier estimated survival after gastric cancer diagnosis by tumor Epstein-Barr virus status; B, overall survival of patients with stage Ⅰ; C, overall survival of patients with stage Ⅱ; D, overall survival of patients with stage Ⅲ; E, overall survival of patients with stage Ⅳ. Abbreviations as in Table 1."

Table 3

Multivariate Cox regression analysis of prognostic factors for gastric cancer patients"

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

Figure 3

Differentially expressed genes and their expression levels in EBVaGC and EBVnGC from the TCGA gastric cancer dataset A, differentially expressed genes of EBVaGC (red: genes of up-regulation; green: genes of down-regulation); B, the expression of SALL4 in EBVaGC and EBVnGC; C, the expression of PD-L1 in EBVaGC and EBVnGC. TCGA, The Cancer Genome Atlas; other abbreviations as in Table 1."

Figure 4

Kaplan-Meier survival curves for SALL4 and PD-L1 differentially expressed in EBVaGC and EBVnGC A, gastric cancer patients with PD-L1 positive with good outcomes; B, gastric cancer patients with SALL4 negative with good outcomes."

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