Clinicopathological features of tumor mutation burden, Epstein-Barr virus infection, microsatellite instability and PD-L1 status in Chinese patients with gastric cancer

Li Zhang,Linxin Zhou,Ziyu Li,Dongliang Wang,Aiwen Wu,Zhongwu Li,Dongmei Lin,Yinkui Wang,Yiqiang Liu

doi:10.1186/s13000-021-01099-y

Abstract

ObjectivesGastric cancer (GC) is the 4th most common type of cancer worldwide. Different GC subtypes have unique molecular features that may have different therapeutic methods. The aim of the present study was to investigate Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, the expression of programmed death-ligand 1 (PD-L1) and gene mutations in GC patients.MethodsThe data of 2504 GC patients, who underwent curative gastrectomy with lymphadenectomy at Peking University Cancer Hospital between 2013 and 2018, were reviewed. We analyzed the clinicopathological factors associated with the immunohistochemistry (IHC) profiles of these patients, and genetic alterations were analyzed using next generation sequencing (NGS).ResultsMismatch repair-deficient (d-MMR) GC patients were found to have a higher probability of expressing PD-L1 (p = 0.000, PD-L1 cutoff value = 1%). In addition, 4 and 6.9% of the 2504 gastric cancer patients were EBV-positive and d-MMR, respectively. The number of MLH1/PMS2-negative cases was 126 (6%), and the number of MSH2/MSH6-negative cases was 14 (0.9%). d-MMR status was associated with a intestinal group (p = 0.012), but not with tumor differentiation. Furthermore, MSI and d-MMR GC status (detected by NGS and IHC, respectively) were consistently high, and the rate of MSI was higher in patients with d-MMR GC. A number of genes associated with DNA damage repair were detected in GC patients with MSI, including POLE, ETV6, BRCA and RNF43. In patients with a high tumor mutation burden, the most significantly mutated genes were LRP1B (79.07%), ARID1A (74.42%), RNF43 (69.77%), ZFHX3 (65.12%), TP53 (58.14%), GANS (51.16%), BRCA2 (51.16%), PIK3CA (51.16%), NOTCH1 (51.16%), SMARCA4 (48.84%), ATR (46.51%), POLE (41.86%) and ATM (39.53%).ConclusionsUsing IHC and NGS, MSI status, protein expression, tumor mutation burden (TMB) and genetic alterations were identified in patients with GC, which provides a theoretical basis for the future clinical treatment of GC.

Highlights

Gastric cancer (GC) is one of the most commonly cancers, which has high mortality worldwide [1]
Using IHC and next generation sequencing (NGS), microsatellite instability (MSI) status, protein expression, tumor mutation burden (TMB) and genetic alterations were identified in patients with GC, which provides a theoretical basis for the future clinical treatment of GC
Association between programmed death-ligand 1 (PD-L1) expression and the clinicopathological features of GC PD-L1-positive cases were defined by the presence of membrane staining in least 1% of tumor cells or tumorinfiltrating immune cells

Summary

Introduction

Gastric cancer (GC) is one of the most commonly cancers, which has high mortality worldwide [1]. Different molecular alterations led to the identification of distinct GC subtypes. GC was divided into four molecular subtypes, which were EBV infection subtype, microsatellite instability (MSI) type, genome stable type and chromosome unstable type [2, 3]. These different subtypes could be used to guide therapeutic practice. The new classification is helpful to the selection of targeted drugs for gastric cancer patients. EBV infection can induce gene hypermethylation and tumorigenesis

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