Brief communicationAssociation of MICA-129 polymorphism with nasopharyngeal cancer risk in a Tunisian population
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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MICA and KLRK1 genes and their impact in cervical intraepithelial neoplasia development in the southern Brazilian population
2020, Human ImmunologyCitation Excerpt :The polymorphism MICA-129 rs1051792, that is responsible for the polymorphic change from Methionine (Met) to Valine (Val) at position 129 in the alfa-2 domain of the MICA was related to the bind Natural Killer Group 2D (NKG2D) receptor with differential affinity leading to impaired function of NK cells [10]. This dimorphism divides the MICA alleles into two groups and it has been associated with several diseases related to Natural Killer cells (NK) activity, under conditions of oxidative stress, viral infection, diverse types of cancer and autoimmune diseases [13–15]. NKG2D is a C-type lectin-like molecule, encoded by the KLRK1 gene, which is an activating receptor expressed by NK cells and T cell subsets [16].
Influence of major histocompatibility complex class I chain-related gene A polymorphisms on cytomegalovirus disease after allogeneic hematopoietic cell transplantation
2020, Hematology/ Oncology and Stem Cell TherapyCitation Excerpt :These are categorized as V/V, M/V, or M/M. These variable affinities have been suggested to affect thresholds of NK cell triggering and T cell modulation and consequently influencing clinical phenotypes in autoimmune disorders and malignancies [11–13]. Given the potential benefit of NK cell alloreactivity for protection from CMV disease after alloHCT, we hypothesized that donor–recipient MICA mismatches and MICA-129 genotypes may influence the incidence of CMV infection and disease in alloHCT recipients.
Nasopharyngeal carcinoma: Genetics and genomics
2019, Nasopharyngeal Carcinoma: From Etiology to Clinical PracticeMICA-129 A/G dimorphism, its relation to soluble mica plasma level and spontaneous preterm birth: A case-control study
2018, Journal of Reproductive ImmunologyMHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study
2017, Biology of Blood and Marrow TransplantationCitation Excerpt :NKG2D binding leads to the activation of NK cells via a Src-PI3 kinase signaling pathway that results in cytotoxicity and release of IFNγ. Allelic variants of MICA have been reported to exhibit large differences in binding affinity to NKG2D [13,14]. These MICA alleles are defined by a dimorphism of a single nucleotide polymorphism (rs1051792 A > G) at position 454 in the third exon of the MICA gene, corresponding to amino acid 129 in the alpha-2 domain of the MICA protein [15].