Elsevier

Human Immunology

Volume 70, Issue 1, January 2009, Pages 45-48
Human Immunology

Brief communication
Association of MICA-129 polymorphism with nasopharyngeal cancer risk in a Tunisian population

https://doi.org/10.1016/j.humimm.2008.10.008Get rights and content

Abstract

Major histocompatibility complex (MHC) class I chain–related A (MICA) molecules mediate natural killer (NK) cell activation and T lymphocyte co-stimulation. A polymorphic methionine (met) to valine (val) variation at amino acid position 129 of the α2 heavy chain domain is in linkage disequilibrium with other allelic changes and seems to categorize MICA alleles into strong and weak binder of NKG2D receptor and thereby to influence effector cell function. We investigated here whether MICA-129 dimorphism is associated with susceptibility to/or resistance against developing nasopharyngeal cancer (NPC). DNA from 130 NPC patients and 180 healthy individuals from Tunisia were genotyped for MICA-129 variation. We found a higher frequency of MICA-129 val/val genotype in patients than in controls (corrected p value = 0.02) that could suggest a tumor escape mechanism because of failure to activate NK cells by MICA-129 val allele or absence of NK cell activation because of absence of MICA-129 met allele in individuals otherwise predisposed to viral/environmental factors.

Introduction

Nasopharyngeal carcinoma (NPC) is a tumor arising from surface epithelial cells that line the nasopharynx; it is characterized by a striking ethnogeographical distribution, with high prevalence in the Southeast Asian and Artic regions as well in North African areas including Tunisia [1], [2]. In Tunisia, similar to other North African regions, patients present with two peak incidences, one at approximately 20 years of age and the other at approximately 40–50 years of age [3]. Epidemiologic studies suggest that etiology of NPC is complex and requires interplay of both genetic and environmental factors. Indeed, while infection by Epstein-Barr virus (EBV) is admitted to be a major risk factor in endemic areas [4], [5], there is evidence that other common environmental chemicals including local dietary factors are associated with NPC development [6]. In terms of genetic factors, besides the molecular events implying tumor suppressor genes, oncogenes, and genes involved in the metabolism of carcinogens and DNA repair [7], [8], several loci of the major histocompatibility complex (MHC) have been be associated with NPC risk [9], [10]. In this context, potential role of the MHC class I chain–related A (MICA) gene belonging to the nonclassical HLA family and located 46 kb centromeric to the human leukocyte antigen (HLA)–B gene is of particular interest.

The MICA gene encodes for HLA-class I–like molecules characterized by an overall tridimensionnal conformation similar to those of their HLA classical counterparts but without an association with β2-microglobulin and antigen presentation function [11], [12]. Given these characteristics, the role of MICA is distinct from HLA class I molecules and does not involve a T cell receptor (TCR)–mediated immune function. Instead, MICA engages NKG2D, a C-type lectin expressed on effector cells including NK, γδ̣ and αβ T cells [13]. Such engagement triggers NK cells and co-simulates T lymphocytes—events known to be crucial in immunopathologic settings such as cancer. MICA expression, induced in cellular stress situations including infections and tumor transformations, was initially believed to be of highly restricted tissue distribution (gastrointestinal epithelium and epithelial tumors), but more recently was demonstrated to be of ubiquitous expression at least at the transcriptional level [14]. The MICA gene, as compared with other HLA class I–like loci, is highly polymorphic, with more than 60 alleles (defined by nucleotide substitutions within exons encoding the three α-domains) described to date. Each of these variants is characterized by the presence of a variable number of short tandem repeats (STRs) within the exon encoding for the transmembrane region of the molecule [15]. A large number of association studies have analyzed the MICA diversity in various diseases, with only a limited number in cancer settings including NPC [16]. More recently, it was demonstrated that a methionine-to-valine change at position 129 of the α2-heavy chain domain categorized MICA alleles into strong (MICA-129 met) and weak (MICA-129 val) binders of NKG2D receptor [17], thereby behaving as an single nucleotide polymorphism (SNP) tag accounting for the other linked polymorphisms. Subsequently, we have shown that the MICA-129 met/met genotype was positively associated with early onset ankylosing spondylitis (AS) independent of HLA-B27 [18]. In this study, we investigated whether this functionally relevant dimorphism of MICA gene influences incidence and evolution of NPC in a phenotypically well-defined patient cohort from Tunisia (North Africa).

Section snippets

Subjects and methods

A total of 130 unrelated patients affected by NPC attending the Institute of Cancer “Salah Azaiz” in Tunis, Tunisia, were included in this study. All patients presented with undifferentiated carcinoma (confirmed by histopathologic analysis) corresponding to clinical stages ranging from I to IV according to the 1997 TNM classification [19]. The gender ratio was 1.6 (80 males/50 females) and the mean age of the disease at diagnosis was 43 years (range, 11–80 years). As a control population group,

Results and discussion

Age-stratified phenotypic characteristics of the studied cohort are summarized in Table 1. As expected for an NPC cohort from north Africa, a characteristic bimodal distribution in terms of incidence was noted, with one peak at 20 years and a second peak around 40 years (Figure 1). At the time of diagnosis, the vast majority of the patients presented an advanced tumor stage (III or IV), with lymph node metastasis, all undergoing the same therapeutic protocol.

We found that MICA-129 val allele

Acknowledgments

This work was supported by institutional funding to INSERM U662 and Assistance Publique des Hôpitaux de Paris (AP-HP) and by French-Tunisian (INSERM-DGRSRT, Tamouza-Guemira) bilateral cooperation.

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