Nasopharyngeal Carcinoma Susceptibility Research Articles

Genetic variants of LncRNAs HOTTIP and MEG3 influence nasopharyngeal carcinoma susceptibility and clinicopathologic characteristics in the Southern Chinese population

ObjectiveRecent studies have indicated that HOTTIP and MEG3 are associated with the initiation and progression of various types of tumors, including nasopharyngeal carcinoma (NPC). This investigation aimed to elucidate the impact of HOTTIP and MEG3 polymorphisms on the susceptibility and clinicopathologic characteristics of NPC.MethodsThis research employed next-generation sequencing and multiplex PCR to assess the polymorphisms of HOTTIP rs1859168 and MEG3 rs7158663 in 200 NPC and 200 healthy individuals respectively. HOTTIP and MEG3 expression were assessed via qRT-PCR assessment. Furthermore, the genotypes and alleles frequency of rs1859168 and rs7158663 were compared between healthy and NPC individuals to elucidate their influence on NPC susceptibility and relation with clinicopathologic characteristics.ResultsIn comparison with the healthy cohort, the presence of HOTTIP rs1859168 CC genotype and the C allele were markedly linked with increased NPC incidence (p < 0.05). Furthermore, the MEG3 rs7158663 AA genotype and the A allele also indicated an increased risk of NPC (p < 0.05). The subgroup analysis of age, EBV infection, gender, nationality, smoking, and drinking status revealed no marked association between rs1859168 and rs7158663 genotypes and these potential confounding factors. Moreover, it was observed that rs1859168 CC and rs7158663 AA genotypes were related to local tumor invasion and lymph node metastasis. Additionally, HOTTIP indicated a marked elevation, while MEG3 substantially reduced in NPC samples than the normal nasopharyngeal biospecimens. Patients who carried CC or CA genotypes rather than the HOTTIP rs1859168 AA genotype, had substantially higher HOTTIP levels, while patients with rs7158663 AA or GA genotypes indicated notably lower expression of MEG3 than GG genotype carriers.ConclusionIndividuals with genetic variants of HOTTIP rs1859168 and MEG3 rs7158663 might have an increased risk of NPC susceptibility and related clinicopathologic characteristics, potentially by affecting the expression of HOTTIP and MEG3.

Genetic variations in CYP2A6, CYP2E1, GSTM1, GSTT1 genes and the risk of Nasopharyngeal carcinoma in North African population.

Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy associated with both genetic and environmental factors. Polymorphic deletions of the phase I and phase II genes involved in the detoxification of potential carcinogens may be a risk factor for nasopharyngeal carcinoma. In this study, we investigated the relationship between CYP2E1 (rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) gene variations and NPC risk in North African countries with the highest incidence of NPC (Morocco, Algeria and Tunisia). and the evaluation of the potential use of these variants as potential biomarkers for NPC management. A total of 600 NPC cases and 545 controls frequency-matched on ethnicity, sex, age and childhood household type, were recruited from three North African countries (Morocco, Algeria and Tunisia) and analysed. Genotyping of CYP2A6 and CYP2E1(rs3813867) was performed by polymerase chain reaction restriction (PCR)-fragment length polymorphism (RFLP) analysis and the GSTM1 (rs1183423000) and GSTT1(rs1601993659) genetic variations were evaluated using the PCR technique. The genotype distributions of CYP2E1(rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) genotypes did not differ significantly among NPC cases and controls (p>0.05). Furthermore, our data did not reveal any association with smoking and the studied variants, even when the samples were stratified by the duration period of smoking. In this large studied North African population, our findings suggest that the functional CYP2E1, CYP2A6, GSTM1 and GSTT1 variations did not influence NPC susceptibility.

Leukocyte immunoglobulin-like receptor A3 gene deletion in five Chinese populations and protective association with nasopharyngeal carcinoma.

Among the thirteen leukocyte Ig-like receptor (LILR) loci located at 19q13.4, LILRA3 is unique in that it encodes a soluble protein lacking the transmembrane and cytoplasmic domains, and a 6.7 kb deletion spanning the first seven exons has been detected in some human individuals. Presently, there is a lack of data about the distribution of LILRA3 gene deletion in more diverse ethnic groups. Also, no previous studies have investigated the correlation between copy number variation (CNV) of LILRA3 and nasopharyngeal carcinoma (NPC). In this study, five populations from China mainland: two Southern Han populations, Hunan (N = 1478) and Guandong (N = 107); one Southeastern Han population, Fujian (N = 439); and two Northern populations, Inner Mongolia Han (N = 104) and Mongol population from Inner Mongolia (N = 158) were investigated for CNV of LILRA3 using polymerase chain reaction-sequence-specific priming (PCR-SSP) method. LILRA3 variants were also examined in a cohort of NPC cases (N = 1142) in Hunan Han population. The five Chinese populations demonstrated northward increase in frequency of the deleted form of LILRA3 gene (LILRA3*Del) (all corrected p values < 0.05). Inter-population comparison also uncovered significant differentiation in the distribution of CNV of LILRA3 among modern human populations. LILRA3*Del was found to confer significantly reduced risk to NPC in Hunan Han population (at allelic level: OR = 0.79, 95% CI = 0.71-0.89, p < 0.0001; at genotype level: OR= 0.63, 95% CI = 0.51-0.79, p < 0.0001). No interaction was found between LILRA3 variants and HLA-A*02:07, HLA-A*11:01, HLA-B*13 and HLA-B*46:01 alleles in susceptibility to NPC. Our study constitutes the first demonstration of LILRA3 gene as a locus linked to NPC susceptibility in a southern Chinese population. Future independent studies in other populations are warranted to confirm the findings reported in this study.

High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR= 0.74, 95% CI= 0.68-0.81, p= 3.08×10-11) and 17q12 (rs226241; OR= 1.42, 95% CI= 1.26-1.60, p= 1.62×10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

Non-Homologous End-Joining Pathway Genotypes Significantly Associated with Nasopharyngeal Carcinoma Susceptibility.

Defects in the non-homologous end-joining (NHEJ) DNA repair pathway lead to genomic instability and carcinogenesis. However, the roles of individual NHEJ genes in nasopharyngeal carcinoma (NPC) etiology are not well-understood. The aim of this study was to assess the contribution of NHEJ genotypes, including XRCC4 (rs6869366, rs3734091, rs28360071, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and Ligase4 rs1805388, to NPC risk, with 208 NPC patients and 416 controls. Genotype-phenotype correlations were also investigated by measuring mRNA and protein expression in adjacent normal tissues and assessing the NHEJ repair capacity in blood lymphocytes from 43 NPC patients. The results showed significant differences in the distributions of variant genotypes at XRCC4 rs3734091, rs28360071, and XRCC6 rs2267437 between the cases and controls. The variant genotypes of these three polymorphisms were associated with significantly increased NPC risks. NPC patients with the risk genotypes at XRCC6 rs2267437 had significantly reduced expression levels of both mRNA and protein, as well as a lower NHEJ repair capacity, than those with the wild-type genotype. In conclusion, XRCC4 rs3734091, rs28360071, and XRCC6 rs2267437 in the NHEJ pathway were associated with NPC susceptibility. XRCC6 rs2267437 can modulate mRNA and protein expression and the NHEJ repair capacity.

LncRNA FAS-AS1 upregulated by its genetic variation rs6586163 promotes cell apoptosis in nasopharyngeal carcinoma through regulating mitochondria function and Fas splicing

Nasopharyngeal carcinoma (NPC) is a common head and neck malignant with a high incidence in Southern China. Genetic aberrations play a vital role in the pathogenesis, progression and prognosis of NPC. In the present study, we elucidated the underlying mechanism of FAS-AS1 and its genetic variation rs6586163 in NPC. We demonstrated that FAS-AS1 rs6586163 variant genotype carriers were associated with lower risk of NPC (CC vs. AA, OR = 0.645, P = 0.006) and better overall survival (AC + CC vs. AA, HR = 0.667, P = 0.030). Mechanically, rs6586163 increased the transcriptional activity of FAS-AS1 and contributed to ectopic overexpression of FAS-AS1 in NPC. rs6586163 also exhibited an eQTL trait and the genes affected by rs6586163 were enriched in apoptosis related signaling pathway. FAS-AS1 was downregulated in NPC tissues and over-expression of FAS-AS1 was associated with early clinical stage and better short-term treatment efficacy for NPC patients. Overexpression of FAS-AS1 inhibited NPC cell viability and promoted cell apoptosis. GSEA analysis of RNA-seq data suggested FAS-AS1 participate in mitochondria regulation and mRNA alternative splicing. Transmission electron microscopic examination verified that the mitochondria was swelled, the mitochondrial cristae was fragmented or disappeared, and their structures were destroyed in FAS-AS1 overexpressed cells. Furthermore, we identified HSP90AA1, CS, BCL2L1, SOD2 and PPARGC1A as the top 5 hub genes of FAS-AS1 regulated genes involved in mitochondria function. We also proved FAS-AS1 could affect Fas splicing isoform sFas/mFas expression ratio, and apoptotic protein expression, thus leading to increased apoptosis. Our study provided the first evidence that FAS-AS1 and its genetic polymorphism rs6586163 triggered apoptosis in NPC, which might have a potential as new biomarkers for NPC susceptibility and prognosis.

Correlation of Epstein-Barr virus copy numbers, MICA expression and rs2596542 variant in nasopharyngeal carcinoma tumour

Major histocompatibility complex class I chain-related A (MICA) is a tumour antigen that is greatly expressed on the surfaces of human malignancies and infection cells, which trigger attachment to immune cells. Although many studies have investigated the role of the MICA rs2596542 variant involved in high risk of hepatocellular carcinoma (HCC), the expression regulation of rs2596542 MICA in nasopharyngeal carcinoma (NPC) susceptibility with the Epstein-Barr virus (EBV) is still ambiguous. Therefore, this study was conducted to elucidate the association of rs2596542C/T and EBV load to MICA expression in NPC tissues. A total of 70 tumour tissues from NPC patients were enrolled in the current study. The genetic variant of rs2596542 was identified by Real-time PCR genotyping, and MICA protein expression was quantified by immunohistochemistry staining. A significant difference was observed in the expression of MICA regarding EBV copy numbers (p&lt;0.01). High expression of MICA presented a considerably lower EBV status. In addition, higher expression of homologous MICA rs2596542 CC was significantly associated with a lower EBV load (p&lt;0.001) thus suggesting a protective role of allele C against the infection of EBV. In summary, rs2596542 MICA plays an important role in the immune response preventing the EBV among NPC patients as well as developing a new predictive biomarker for virus susceptibility to cancers.

LMP1-EBV Gene Deletion Mutations and HLA Genotypes of Nasopharyngeal Cancer Patients in Vietnam.

Nasopharyngeal carcinoma (NPC) is the most common cancer among head and neck cancers in Vietnam. We aimed to identify the rate of a 30 bp deletion mutation of the LMP1-EBV gene in nasopharyngeal biopsy tissue samples, the HLA genotypes of NPC patients, and the relationship between these two targets. Patients with NPC at Can Tho Oncology Hospital from September 2014 to December 2018 were selected. A length of 30 bp of the del-LMP1-EBV gene was analyzed using a PCR technique, and the HLA genotypes in patients' blood samples were analyzed with PCR-SSO technology. HLA-B*15 gene carriers had the highest risk of 30 bp LMP1-EBV gene deletion mutation, which was found in 51 out of 70 patients (72.9%). Carriers of the HLA-B*15 allele had a 4.6-fold increased risk of a 30 bp del-LMP1-EBV gene compared with non-carriers of this allele. The initial identification of NPC was related to the 30 bp del-LMP1-EBV gene and high frequencies of the -A*02, -B*15, -DRB1*12, -DQB1*03, and -DQA1*01 HLA alleles. Our study results suggest an association of the 30 bp del-LMP1-EBV gene and the HLA-B*15 allele with NPC susceptibility.

EXPRESSIONS OF PERCEIVED SUSCEPTIBILITY TOWARD NASOPHARYNGEAL CARCINOMA

Introduction: Perceived susceptibility to diseases influences intentions to undertake health protective measures. Methods: The study investigated perceived susceptibility of nasopharyngeal carcinoma (NPC) among Malaysians, focusing on their expressions of disease susceptibility before and after reading an NPC health pamphlet. Method: A total of 65 participants in Kuching and Kota Samarahan, Malaysia, aged 13 to 65, were interviewed on their perceptions of their risk of getting NPC. Results: The thematic analysis of the interviews revealed several levels of perceived susceptibility to NPC, namely, 1) not susceptible to NPC, 2) may be susceptible to NPC, 3) susceptible to NPC, and 4) not knowing much about susceptibility to NPC. The expressions the participants used revolved around “living a healthy life”, “second-hand smoker”, “polluted air” and “eat preserved or salted food”, indicating perceived risk factors of NPC. Conclusion: Some mentioned family history and ethnic background as risk factors. After reading the NPC pamphlet, the participants gave the same reasons but with more specific details on the symptoms and types of food associated with NPC. The study indicated that the NPC pamphlet can increase awareness of NPC because additional reasons given for NPC susceptibility after reading the pamphlet were signs of cancer, age, and NPC incidence in Malaysia.

Associations between ALDH Genetic Variants, Alcohol Consumption, and the Risk of Nasopharyngeal Carcinoma in an East Asian Population.

Nasopharyngeal carcinoma (NPC) and alcohol flush syndrome are thought to be strongly influenced by genetic factors and are highly prevalent amongst East Asians. Diminished activity of aldehyde dehydrogenase (ALDH), a major enzyme in the alcohol-metabolizing pathway, causes the flushing syndrome associated with alcoholic consumption. The genetic effect of ALDH isoforms on NPC is unknown. We therefore investigated the association between the genetic polymorphisms of all 19 ALDH isoforms and NPC among 458 patients with NPC and 1672 age- and gender-matched healthy controls in Taiwan. Single-nucleotide polymorphisms (SNPs) located between the 40,000 base pairs upstream and downstream of the 19 ALDH isoform coding regions were collected from two genome-wise association studies conducted in Taiwan and from the Taiwan Biobank. Thirteen SNPs located on ALDH4A1, ALDH18A1, ALDH3B2, ALDH1L2, ALDH1A2, and ALDH2 Glu487Lys (rs671) were associated with NPC susceptibility. Stratification by alcohol status revealed a cumulative risk effect for NPC amongst drinkers and non-drinkers, with odds ratios of 4.89 (95% confidence interval 2.15–11.08) and 3.57 (1.97–6.47), respectively. A synergistic effect was observed between SNPs and alcohol. This study is the first to report associations between genetic variants in 19 ALDH isoforms, their interaction with alcohol consumption and NPC in an East Asian population.

FTO Gene Polymorphisms Contribute to the Predisposition and Radiotherapy Efficiency of Nasopharyngeal Carcinoma.

BackgroundNasopharyngeal carcinoma (NPC) is mainly concentrated in East and Southeast Asia. This study aims to elucidate the potential associations of functional SNPs in the fat mass and obesity associated gene (FTO) with NPC risk and radiotherapy outcomes in a Chinese population.MethodsFunctional SNP rs1477196 G>A, rs9939609 T>A, rs7206790 C>G, and rs8047395 A>G were genotyped and evaluated for their associations with NPC risk and radiotherapy outcomes.ResultsBoth rs9939609 (allele A versus allele T: OR=1.59; 95% CI=1.17–2.17; P-value=0.003) and rs8047395 (allele G versus allele A: OR=0.76; 95% CI=0.64–0.9; P-value=0.002) were significantly associated with risk of NPC. GTEx showed risk allele A of rs9939609 and rs8047395 were significantly associated with higher FTO mRNA levels in skeletal muscle tissue, which also corroborated our findings. Meanwhile, both rs1477196 (allele A versus allele G: OR=1.64; 95% CI=1.09–2.49; P-value=0.019) and rs9939609 (allele A versus allele T: OR=0.61; 95% CI=0.43–0.87; P-value=0.006) were significantly associated with complete remission (CR) of NPC.ConclusionOur study identified that FTO polymorphisms contributed to the susceptibility and radiotherapy efficacy of NPC. These results shed light on the potential of establishing markers for predicting risk and personalized treatment of NPC.

A Systematic Review of Epstein-Barr Virus Latent Membrane Protein 1 (LMP1) Gene Variants in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is an aggressive tumor with a complex etiology. Although Epstein–Barr virus (EBV) infection is known environmental factor for NPC development, the degree to which EBV naturally infects nasopharyngeal epithelium and the moment when and why the virus actively begins to affect cell transformation remains questionable. The aim of this study was to explore the association between LMP1 gene variability and potential contribution to NPC development. A systematic review was performed through searches of PubMed, Web of Science (WoS) and SCOPUS electronic databases. Additionally, meta-analysis of the difference in the frequency of seven LMP1 gene variants in NPC and control individuals was accomplished. The results from this study give a proof of concept for the association between 30 bp deletion (OR = 3.53, 95% CI = 1.48–8.43) and Xhol loss (OR = 14.17, 95% CI = 4.99–40.20) and NPC susceptibility when comparing biopsies from NPC and healthy individuals. Otherwise, 30 bp deletion from NPC biopsies could not distinguish NPC from EBV-associated non-NPC tumors (OR = 1.74, 95% CI = 0.81–3.75). However, B95-8, China1 and North Carolina variants were uncommon for NPC individuals. Much more efforts remains to be done to verify the biological significance of the differences observed, define so-called “high-risk” EBV variants and make it available for clinical application.

Genetic Polymorphisms of Long Non-coding RNA Linc00312 Are Associated With Susceptibility and Predict Poor Survival of Nasopharyngeal Carcinoma.

BackgroundLinc00312 is dysregulated in nasopharyngeal carcinoma (NPC) and participates in the initiation and progression of NPC. Our previous studies suggested that linc00312 was able to enhance the sensitivity of NPC cells to irradiation and NPC patients with higher expression of linc00312 was associated with better short-term curative effect and overall survival. The single nucleotide polymorphisms (SNPs) of lncRNAs may influence the disease course and outcome by affecting the expression, secondary structure or function of lncRNAs. However, the role of SNPs in linc00312 on the occurrence and survival of NPC remains unknown.MethodsWe recruited 684 NPC patients and 823 healthy controls to evaluate the association between linc00312 SNPs and NPC susceptibility by using multivariate logistic regression analysis. Kaplan-Meier analysis and Cox proportional hazards regression were applied to assess the effect of linc00312 SNPs on the survival of NPC patients. The relative expression of linc00312 in NPC tissues was determined by real-time PCR. The interaction between linc00312 and mir-411-3p was explored by luciferase reporter assay. In silico prediction of the changes on linc00312 folding structure was conducted by RNAfold WebServer.ResultWe demonstrated that rs12497104 (G > A) GA genotype carriers had a higher risk than others for suffering from NPC (GA vs GG, OR = 1.437, P = 0.003). Besides, patients with rs12497104 AA genotype showed a poorer overall survival in contrast to GG genotype (AA vs GG, HR = 2.117, P = 0.011). In addition, the heterozygous carriers of rs15734 (G > A) and rs164966 (A > G) were correlated with decreased risk of NPC (GA vs GG, OR = 0.778, P = 0.031; GA vs AA, OR = 0.781, P = 0.033, respectively). We found that the three SNPs might influence the expression of linc00312 in a genotype specific feature. The local centroid secondary structure as well as the minimum free energy of linc00312 were changed following the candidate SNPs alterations. Besides, we revealed that the G to A alteration at rs12497104 disrupted the binding between mir-411-3p and linc00312.ConclusionOur results indicated genetic polymorphisms of linc00312 might serve as potential biomarkers for NPC carcinogenesis and prognosis.

Association between HLA alleles and Epstein-Barr virus Zta-IgA serological status in healthy males from southern China.

BackgroundNasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta‐IgA, in healthy males from NPC endemic area.MethodsHLA alleles of 1078 healthy males in southern China from the 21‐RCCP study were imputed using genome‐wide single nucleotide polymorphism data. EBV Zta‐IgA in blood samples were measured using an enzyme‐linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta‐IgA serological status and its potential joint association with smoking. The binding affinity for Zta‐peptide was predicted using NetMHCIIpan 4.0.ResultsHLA‐DRB1*09:01 was found to be associated with a higher risk of Zta‐IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32–2.45; p = 1.82 × 10−4). Compared with non‐smokers without HLA‐DRB1*09:01, the effect size increased to 2.19‐ and 3.70‐fold for the light and heavy smokers carrying HLA‐DRB1*09:01, respectively. Furthermore, HLA‐DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA‐DRB1 alleles.ConclusionsOur study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA‐DRB1*09:01 have a significantly higher risk of being Zta‐IgA seropositive, which indicates the necessity of smoking cessation in certain high‐risk populations and also provide clues for further research on the etiology of NPC.

Genetic variants in NKG2D axis and susceptibility to Epstein-Barr virus-induced nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a rare epithelial carcinoma arising from the nasopharyngeal region. The pathogenesis of NPC is linked to Epstein-Barr virus (EBV) infection, although genetics and lifestyle factors appears to be also implicated. NKG2D is an immunoreceptor expressed by NK and T-cell subsets that recognizes MICA protein and other ligands on tumor cells. NKG2D interaction with MICA plays a role in the immunosurveillance to viruses and cancer. We investigated potential associations between functional polymorphisms in NKG2D and MICA genes with NPC susceptibility. We conducted a case-control study including 255 Vietnamese patients with EBV + non-differentiated NPC and 220 healthy controls. We observed a significant association between the LNK/LNK genotype of rs1049174 (a variant associated with lower NKG2D receptor expression and reduced NK cell cytotoxicity) and increased susceptibility to NPC (adjusted OR = 1.66, 95% CI 1.07-2.59; p = 0.024). Similarly, the AA genotype of MICA rs2596542 was significantly associated with NPC (adjusted OR = 2.12; 95% CI 1.22-3.81; p = 0.009). In addition, tumor specimens of NPC patients with the AA genotype displayed a higher expression level of MICA proteins and showed higher EBV titers compared with tumor tissues from patients with the GG or GA genotypes. Higher EBV copy numbers were also observed in tumors with the A allele of MICA rs1051792 (also known as MICA-129 Met/Val) compared with those with the G allele; however, MICA rs1051792 variants were not associated with NPC susceptibility. These results suggest that genetic variants in components of the NKG2D axis may influence the individual susceptibility to EBV-induced NPC.

Single nucleotide polymorphisms within NFKBIA are associated with nasopharyngeal carcinoma susceptibility in Chinese Han population

Genes involved in latent membrane protein 1 (LMP1) signaling pathways have been suggested to play an important role in nasopharyngeal carcinogenesis. We investigated potentially functional genetic variants associated with the risk of nasopharyngeal carcinoma (NPC) in genes involved in the LMP1 signaling pathway. Altogether, 73 single nucleotide polymorphisms (SNPs) with MAF ≥ 10% were located within the regions of interest of the four genes TRAF3, NFKBIA, CHUK and MAP2K4. From these, 10 SNPs were selected for genotyping based on LD (r2 ≥ 0.80) in a hospital-based case-control study of 332 NPC cases and 585 healthy controls from the Chinese Han population. Minor allele carriers of the promoter SNP rs2233409 in NFKBIA, had an increased risk of NPC (AA vs GG: OR 7.14, 95%CI, 1.08–34.18, P = 0.04, dominant model). Based on the results, we concluded that rs2233409 polymorphism in NFKBIA may be moderately associated with the risk of NPC. Further studies with larger independent samples and functional analysis are needed to verify our results.

Functional Study of Polymorphism 1888 C>T in the Promoter Region of Human PLUNC Gene

BackgroundOur previous study showed that a single nucleotide polymorphisms (SNP) of 1888 C>T located at promoter region of human PLUNC gene might affect the susceptibility of nasopharyngeal carcinoma (NPC) in a Chinese population. This study aims to analyze the effect of the genetic variant on PLUNC promoter activity. Materials and methodsThe DNA fragments of the PLUNC promoter region including the SNP 1888 C>T were obtained by polymerase chain reaction (PCR). The recombinant plasmid of the fragment and the pGL3-Enhancer firefly luciferase reporter vector were cloned and identified. Relative luciferase activity (RLA) was measured and electrophoretic mobility shift assay (EMSA) was analyzed. ResultsLuciferase reporter assays demonstrated that luciferase activity of the 1888 T-allele was significantly higher, compared with the C-allele. EMSA experiment proved that the PLUNC gene promoter region SNP 1888 TT genotype had the ability to bind the nucleus protein with the human NPC CEN2 cell, whereas the CC genotype had not. ConclusionsSNP 1888 C>T in the promoter region of PLUNC gene might be a functional mutant locus, indicating that individuals carrying SNP 1888 C-C genotype might be more likely to develop NCP due to the reduced expression of the PLUNC gene. Further functional studies on PLUNC genetic variants are warranted to verify our findings.

Genetic Polymorphisms Along with Dietary and Environmental Factors Enhance the Susceptibility to Nasopharyngeal Carcinoma in Nagaland of Northeast India.

This study investigated the association of seven widely known DNA repair gene polymorphisms (hOGG1 Ser326Cys, XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln, XPC Val499Ala, XPD Lys751Gln and ERCC1 Cys8092Ala) with dietary and environmental factors for Nasopharyngeal Carcinoma (NPC) susceptibility in Nagaland of Northeast India. The genotypes were determined in 128 NPC patients and 180 healthy controls by PCR-RFLP. XRCC1 Arg280His, XPC Val499Ala and ERCC1 Cys8092Ala were found to be associated with NPC risk. Tobacco smoking and burning of firewood for cooking were also found to be a risk factor for NPC. The haplotype analysis of five single-nucleotide polymorphisms (SNPs) XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln, XPD Lys751Gln and ERCC1 Cys8092Ala identified haplotype TGAAC to be significantly associated with NPC. Multifactor dimensionality reduction (MDR) analysis suggested ERCC1 Cys8092Ala to be the best one-factor model that could predict NPC risk. From this study, we conclude that examining the synergistic interactions of various gene-environmental factors together is a better approach to understand NPC susceptibility, instead of their individual effects.

Association between variant alleles of major histocompatibility complex class II regulatory genes and nasopharyngeal carcinoma susceptibility.

Major histocompatibility complex (MHC) class II regulatory genes play a paramount role in immune response that can exert a predominant influence on clinical outcome of Epstein-Barr virus infection consistently assumed as the main pathogenetic factor for nasopharyngeal carcinoma. To elucidate the relationship between allelic variants of MHC class II regulatory genes and susceptibility to nasopharyngeal carcinoma, a total of 28 polymorphic loci at MHC class II regulatory genes, involving CIITA, CREB1, RFX family genes (RFX5, RFXAP, and RFXANK), and NFY family genes (NFYA, NFYB, and NFYC), were genotyped by multiplex SNaPshot minisequencing in 137 patients with nasopharyngeal carcinoma and 107 healthy controls from the southern Chinese population. Allelic analysis disclosed that rs7404873, rs6498121, rs6498126, and rs56074043 shared correlations with nasopharyngeal carcinoma (Ptrend < 0.05). Further, rs6498126 on CIITA was independently associated with the risk of developing nasopharyngeal carcinoma (CC vs. GG, odds ratio: 7.386, 95% confidence interval: 1.934-28.207, Ptrend < 0.01). Conversely, rs7404873 on CIITA and rs56074043 on NFYB manifested epistatic interaction to decreased susceptibility of nasopharyngeal carcinoma (rs7404873, TT vs. GG, odds ratio: 0.256, 95% confidence interval: 0.088-0.740, Ptrend < 0.05; rs56074043, AA vs. AG, odds ratio: 0.341, 95% confidence interval: 0.129-0.900, Ptrend < 0.05). Additionally, bioinformatics analysis revealed that the three variants were transcriptional regulatory in function and might impact the expression of nearby genes. The findings suggested genetic variants on MHC class II regulatory genes contributed to nasopharyngeal carcinoma susceptibility and might provide new insights for screening high-risk population.

Association of regenerating gene 1A single-nucleotide polymorphisms and nasopharyngeal carcinoma susceptibility in southern Chinese population

ObjectiveNasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia. Genetic susceptibility is a major contributing factor in determining the individual risk of NPC in these areas. To test the association between NPC and variants in regenerating gene 1A (REG1A), we conducted a hospital-based case–control study in a Cantonese-speaking population from Guangdong province.MethodsWe endeavored to determine whether genetic variants of the REG1A gene were associated with the risk of NPC amidst the Cantonese population in a hospital-based case–control study using polymerase chain reaction-restriction and direct sequencing analysis in 211 NPC patients and 150 healthy controls. The association between NPC risk and the 14C/T, 20C/T, 369G/T, 1201A/G, and 2922C/T polymorphisms was examined after adjustment for age and sex.ResultsWe found an increased risk of developing NPC in individuals with REG1A 2922C/T variant genotype (p = 0.003, OR 0.419, 95% CI 0.235–0.746), and after adjustment for sex and age (p = 0.003, OR 0.406, 95% CI 0.226–0.732). No association between other polymorphisms (14C/T, 20C/T, 369G/T, and 1201A/G) and the risk of NPC was observed, before or after adjustment for age and sex.ConclusionOur findings suggest that the REG1A 2922C/T polymorphism is associated with an increased risk of developing NPC in a Cantonese population from Guangdong province. Larger studies are required to confirm our findings and unravel the underlying mechanisms.