Further evidence for the existence of major susceptibility of nasopharyngeal carcinoma in the region near HLA-A locus in Southern Chinese

Abstract

BackgroundNasopharyngeal carcinoma (NPC) is a multi-factorial malignancy closely associated with environmental factors, genetic factors and Epstein-Barr virus infection. Human leukocyte antigen (HLA) complex, specially the region near HLA-A locus, was regarded as a major candidate region bearing NPC genetic susceptibility loci in many previous studies including two recent genome-wide association (GWA) studies. To provide further evidence for the NPC susceptibility in the region near HLA-A locus based on other previous studies, we carried out a two-stage hospital-based case control association study including 535 sporadic NPC patients and 525 cancer-free control subjects from Guangdong, a high prevalence area of NPC in China.Methods38 tag SNPs were initially selected by Heploview from the segment around HLA-A locus (from D6S211 to D6S510) and genotyped on GenomeLab SNPstream platform in 206 cases and 180 controls in the stage 1. Subsequently, the stage 1 significant SNPs and 17 additional SNPs were examined on another platform (Sequenom iPlex Assay) in another independent set of study population including 329 cases and 345 controls.ResultsTotally eight SNPs from the segment from D6S211 to D6S510 within HLA complex were found to be significantly associated with NPC. Two of the most significant SNPs (rs9260734 and rs2517716) located near to HLA-A and HCG9 respectively were in strong LD with some other SNPs of this region reported by two previous GWA studies. Meanwhile, Meanwhile, novel independent susceptibility loci (rs9404952, Pcombined = 6.6 × 10-5, OR combined = 1.45) was found to be close to HLA-G.ConclusionTherefore, our present study supports that the segment from D6S211 to D6S510 in HLA complex region might contain NPC susceptibility loci which indeed needs to be fully investigated in the future.

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response

“…And we conducted a sequencing‐based association analysis through LRT and the Fisher's exact test and identified 5066 SNPs with significant evidence ( P  < .05, Figure 1A,B, Table S2). Notably, these variants include most of signals previously reported by two GWAS efforts6, 7 and our previous study (Table S3),5 indicating the reliability of our results.…”

“…Furthermore, we calculated the linkage disequilibrium (LD) between the top SNP rs117565607 with the previously reported SNPs5, 6, 7 associated with NPC in MHC region in the 1000 Genomes Project Phase 3 data. As shown in Table S7, very low correlations were identified between rs117560607 with those SNPs, with the largest R 2 of 0.0339 between rs117565607 and rs3129055 (near HLA‐F gene), and SNP rs3129055 was found to have a significant association with NPC in the Taiwanese population 6.…”

“…It comprises more than 200 classical and nonclassical MHC genes that have long been believed to be involved in infection, inflammation, autoimmunity, and various cancers 4. Since the 1970s, numerous efforts have been made to reveal the association of the MHC with NPC, hypothesizing that some MHC loci or genes may play major roles in the genetic predisposition to NPC, probably either by modulating innate and adaptive immune responses or as genetic markers of predisposition loci in close linkage 2, 5. This was also strongly supported by two genomewide association studies (GWAS)6, 7 and our recent association study 5.…”

“…Since the 1970s, numerous efforts have been made to reveal the association of the MHC with NPC, hypothesizing that some MHC loci or genes may play major roles in the genetic predisposition to NPC, probably either by modulating innate and adaptive immune responses or as genetic markers of predisposition loci in close linkage 2, 5. This was also strongly supported by two genomewide association studies (GWAS)6, 7 and our recent association study 5. Despite the success of GWAS in identifying genetic variations, the variations in the genome have small effect sizes and only explain a modest fraction of the predicted genetic variance 8.…”

Co-treatment with arsenic trioxide and ganciclovir reduces tumor volume in a murine xenograft model of nasopharyngeal carcinoma

“…Most cases in endemic areas consist of WHO Type III anaplastic NPC with a high correlation of Epstein Barr virus (EBV) positivity while the majority of cases in non-endemic areas consist of keratinizing squamous cell carcinomas [5-9]. The genetic and geographic pattern to NPC occurrence rates indicates multifocal etiology in that those of Cantonese descent born in North America display occurrence rates greater than their geographical counterparts, but less than that in endemic areas [10-15]. …”