Epstein-Barr virus and mismatch repair deficiency status differ between oesophageal and gastric cancer: A large multi-centre study

Abstract

BackgroundOesophageal (OeC) and gastric (GC) cancer patients are treated with similar multimodal therapy and have poor survival. There remains an urgent clinical need to identify biomarkers to individualise patient management and improve outcomes. Therapy with immune checkpoint inhibitors has shown promising results in other cancers. Proposed biomarkers to predict potential response to immune checkpoint inhibitors include DNA mismatch repair (MMR) and/or Epstein–Barr virus (EBV) status. The aim of this study was to establish and compare EBV status and MMR status in large multi-centre series of OeC and GC.MethodsEBV was assessed by EBV-encoded RNA (EBER) in situ hybridisation and MMR protein expression by immunohistochemistry (IHC) in 988 OeC and 1213 GC from multiple centres. In a subset of OeC, microsatellite instability (MSI) was tested in parallel with MMR IHC.ResultsFrequency of MMR deficiency (MMRdef) and MSI was low in OeC (0.8% and 0.6%, respectively) compared with GC (10.3%). None of the OeCs were EBER positive in contrast to 4.8% EBER positive GC. EBV positive GC patients were younger (p = 0.01), more often male (p = 0.001) and had a better overall survival (p = 0.012). MMRdef GC patients were older (p = 0.001) and showed more often intestinal-type histology (p = 0.022).ConclusionsThis is the largest study to date indicating that EBV and MMRdef do not play a role in OeC carcinogenesis in contrast to GC. The potential clinical usefulness of determining MMRdef/EBV status to screen patients for eligibility for immune-targeting therapy differs between OeC and GC patients.

Preservation of Epstein–Barr virus status and mismatch repair protein status along the metastatic course of gastric cancer

“…We therefore analysed EBV and MMR protein status in the primary tumours and corresponding metastases in a large western cohort of resected primary GC. The frequency of EBV‐positive and MMR‐deficient tumours in our cohort is slightly lower compared to GC cohorts in previous publications, where EBV‐positive tumours occurred in a range of between 4 and 14% and MMR‐deficient tumours between 8 and 26% 5,7‐11,16 . We hypothesise that the observed differences of EBV frequency are due mainly to the different patient populations under study, and reflect the known geographical variation in EBV positivity, with both ethnicity and lifestyle as well as environmental risk factors and coinfections as contributing factors 17 .…”

“…Loss of MSH2 and MSH6 expression was not observed. We did not identify any tumour that was both EBV‐positive and MMR‐deficient, a rare phenomenon that has been described previously in one of 799 cases of a western GC cohort 11 . Intratumoural heterogeneity of EBV or MMR status between tumour front and tumour centre was not observed.…”

“…In particular, identification of EBV‐positive and MSI tumours can be accomplished by using Epstein–Barr‐encoding region (EBER) in‐situ hybridisation and mismatch repair (MMR) protein (MLH1, PMS2, MSH2 and MSH6) immunohistochemistry 8‐10 . The concordance rate of MMR expression profiles by immunohistochemistry and microsatellite instability testing has been shown to be as high as 99% for GC 11 . Thus, these techniques may represent a convenient screening tool for patient stratification in the clinical setting and to study cohorts of GC that differ from the TCGA and ACRG cohorts regarding patient ethnicity, geographic distribution risk factors and tumour stage.…”

Prognostic implication of molecular subtypes and response to neoadjuvant chemotherapy in 760 gastric carcinomas: role of Epstein–Barr virus infection and high‐ and low‐microsatellite instability

“…If there is no MSI, the tumour is considered as microsatellite stable (MSS). MSI‐H is related to DNA mismatch repair deficiency and is detected in about 7–24% of GC . MSI‐H has been related to good prognosis in GC in the majority of studies, but conflicting results of the prognostic significance for patients treated with CTx have been described .…”

“…Another subgroup of the TCGA classification is formed by Epstein–Barr virus positive (EBV(+)) tumours, which represent about 4–10% of GC .…”