Molecular profiling of gastric cancer in a population with high HIV prevalence reveals a shift to MLH1 loss but not the EBV subtype

Abstract

The human immunodeficiency virus (HIV) pandemic heavily affects sub-Saharan Africa. It is associated with persistently active Epstein-Barr virus (EBV) infection.To determine if this translates into increased frequency of EBV-associated gastric cancer (EBVaGC), we evaluated molecular profiles of gastric cancer (GC) in Zambia.Patients with GC or premalignant gastric lesions were enrolled in Lusaka, Zambia.We used patients without any of these lesions as a control group. Chromogenic in situ hybridization (CISH) on tumor tissue was used to identify EBVaGC. To identify the microsatellite unstable subtype, immunofluorescence staining for MutL homolog 1 (MLH1) was used. Exposure to EBV and HIV was assessed serologically. We enrolled 369 patients (median age 52 years ; 198 (54%) female). Of these, 72 (20%) had GC and 35 (9%) had gastric premalignant lesions (PL). CISH identified EBVaGC in 5/44 (11%) of those with adequate tissue, while MLH1 loss was identified in 29/45 (64%). Both GC and PL were associated with the highest titers of antibodies to Early antigen-diffuse (OR 2.5, 95% CI 1.0-6.1, P = .048 and OR 3.9, 95% CI 1.1-12.9, P = .03, respectively) at high concentrations. Human immunodeficiency virus infection was associated with a range of antibodies to EBV, but not with any cancer subtype. Despite the association of HIV with persistent EBV, the proportion of EBVaGC in Zambia is similar to populations with a low prevalence of How to cite this article: Kayamba V, Butt J, Waterboer T, et al. Molecular profiling of gastric cancer in a population with high HIV prevalence reveals a shift to MLH1 loss but not the EBV subtype.

Antibodies Against Epstein–Barr Virus as Disease Markers of Gastric Cancer: A Systematic Review

“…Some studies evaluated different antibody isotypes, but IgM was generally negative, so only IgA and IgG isotypes provided meaningful data. Three studies 24 , 26 , 27 that did not specifically indicate the isotype tested were assumed to represent IgG data. When the authors did not specify which anti-EBNA was measured, we assigned it to EBNA1.…”

“…Right panel: Forest plot showing reported odds ratios (ORs) and respective 95% confidence interval and symbol area representing the number of subjects included for associations with high antibody titers. The studies by Aragones et al, 26 Varga et al, 24 and Kayamba et al 27 did not specify the antibody isotype and were assigned to IgG. Schetter et al , 36 Varga et al , 24 and Pachnia et al 39 did not specify which EBNA or EA antigen was assessed and were assigned to EBNA1 and EA-D, respectively.…”

“…Several studies also compared GC of unknown EBV status versus other gastric lesions. There were 9 of these studies, 24 , 26 , 27 , 34 – 39 which included NAG, AG, IM, DYS, GC, and HC ( Figure 3 ). A total of 9037 individuals (2571 with GC, 1328 with gastritis, 246 with IM, 60 with DYS, 93 patients with unclassified dyspeptic symptoms but without evidence of GC, and 4739 HC) were recruited from 8 countries (3697 from China, 2352 from Spain, 804 from Japan, 716 from Korea, 642 from Mexico, 510 from Zambia, 216 from Paraguay, and 100 from Poland).…”

“…Both studies by Kayamba and collaborators 27 , 35 compared patients with GC and patients with either NAG or patients with unclassified dyspeptic symptoms. Both comparisons found a positive association with EA-D. One of these studies 35 also observed a correlation with EBNA1.…”

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“…According to some studies, human immunodeficiency virus infection was associated with a microsatellite unstable tumor. Thus a study reveals a shift to MLH1 loss in gastric cancer with high HIV prevalence [19][20][21].…”