A Genome Wide Study of Copy Number Variation Associated with Nasopharyngeal Carcinoma in Malaysian Chinese Identifies CNVs at 11q14.3 and 6p21.3 as Candidate Loci

Abstract

BackgroundNasopharyngeal carcinoma (NPC) is a neoplasm of the epithelial lining of the nasopharynx. Despite various reports linking genomic variants to NPC predisposition, very few reports were done on copy number variations (CNV). CNV is an inherent structural variation that has been found to be involved in cancer predisposition.MethodsA discovery cohort of Malaysian Chinese descent (NPC patients, n = 140; Healthy controls, n = 256) were genotyped using Illumina® HumanOmniExpress BeadChip. PennCNV and cnvPartition calling algorithms were applied for CNV calling. Taqman CNV assays and digital PCR were used to validate CNV calls and replicate candidate copy number variant region (CNVR) associations in a follow-up Malaysian Chinese (NPC cases, n = 465; and Healthy controls, n = 677) and Malay cohort (NPC cases, n = 114; Healthy controls, n = 124).ResultsSix putative CNVRs overlapping GRM5, MICA/HCP5/HCG26, LILRB3/LILRA6, DPY19L2, RNase3/RNase2 and GOLPH3 genes were jointly identified by PennCNV and cnvPartition. CNVs overlapping GRM5 and MICA/HCP5/HCG26 were subjected to further validation by Taqman CNV assays and digital PCR. Combined analysis in Malaysian Chinese cohort revealed a strong association at CNVR on chromosome 11q14.3 (Pcombined = 1.54x10-5; odds ratio (OR) = 7.27; 95% CI = 2.96–17.88) overlapping GRM5 and a suggestive association at CNVR on chromosome 6p21.3 (Pcombined = 1.29x10-3; OR = 4.21; 95% CI = 1.75–10.11) overlapping MICA/HCP5/HCG26 genes.ConclusionOur results demonstrated the association of CNVs towards NPC susceptibility, implicating a possible role of CNVs in NPC development.

MICAGene Deletion in 3411 DNA Samples from Five Distinct Populations in Mainland China and Lack of Association with Nasopharyngeal Carcinoma (NPC) in a Southern Chinese Han population

“…In our current study, we did not observe the overall association between MICA*Del and NPC recently reported in a Taiwan Chinese population and a Malaysian Chinese cohort (Tse et al., ; Low et al., ). Further stratified analysis also failed to disclose any gender‐specific association between MICA*Del with NPC as reported in a Taiwan Chinese population (Tse et al., ).…”

“…Recently, deletion of the MICA / HCP5 region was reported with an increased NPC risk among males in Taiwan Chinese population (Tse et al., ). Very recently, a suggestive association between deletion of the segment spanning MICA/HCP5/HCG26 genes and NPC was observed in a Malaysian Chinese cohort but not in a Malaysian Malay cohort (Low et al., ). However, MICA*Del did not exhibit any statistical association with NPC in an earlier study containing 218 NPC patients and 196 healthy controls from a southern Chinese Han population (Tian et al., ).…”

Significance and Distribution of the Mic a/B Alleles Among the Worldwide Populations

“…Such MIC variations are widely reported in worldwide populations such as Chinese [33,48,49,50], Indian [51], Iranian [52,53], Swedish [54], Finnish [55], Korean [56,57], Spanish [58], Bolivian [59], and Algerian [60]. …”

Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks

“…The association of MICA-129 with psoriasis (32) has been disproven in large GWAS cohorts (71). However, associations with NPC (33) and HCC (34) are supported by GWAS data pointing to the MICA gene region (44–46). …”

“…However, since the MICA-129Met/Val dimorphism is functional, it could also indicate that we need to better understand this function to predict its consequences in the pathophysiology of different diseases in various populations, which might be exposed to different interfering environmental factors. This assumption is supported by genome-wide association studies (GWAS), which have assigned disease risks for NPC (44), HCC (45, 46), cervical cancer (47, 48), and asthma (49) or advantages, such as HIV long-term non-progression (50) to the MICA gene region in an unbiased manner.…”