Yuming Zheng

Evaluation of nonviral risk factors for nasopharyngeal carcinoma in a high-risk population of Southern China.

To understand the role of environmental and genetic influences on nasopharyngeal carcinoma (NPC) in populations at high risk of NPC, we have performed a case‐control study in Guangxi Province of Southern China in 2004–2005. NPC cases (n = 1,049) were compared with 785 NPC‐free matched controls who were seropositive for IgA antibodies (IgA) to Epstein‐Barr virus (EBV) capsid antigen (VCA)—a predictive marker for NPC in Chinese populations. A questionnaire was used to capture exposure and NPC family history data. Risk factors associated with NPC in a multivariant analysis model were the following: (i) a first, second or third degree relative with NPC [attributable risk (AR)= 6%, odds ratio (OR) = 3.1, 95% confidence interval (CI) = 2.0–4.9, p < 0.001]; (ii) consumption of salted fish 3 or more than 3 times per month (AR = 3%, OR = 1.9, 95% CI = 1.1–3.5, p = 0.035); (iii) exposure to domestic wood cooking fires for more than 10 years (AR = 69%, OR = 5.8, 95% CI = 2.5–13.6, p < 0.001); and (iv) exposure to occupational solvents for 10 or less years (AR = 4%, OR = 2.6, 95% CI = 1.4–4.8, p = 0.002). Consumption of preserved meats or a history of tobacco smoking were not associated with NPC (p > 0.05). We also assessed the contribution of EBV/IgA/VCA antibody serostatus to NPC risk—32.2% of NPC can be explained by IgA+ status. However, family history and environmental risk factors cumulatively explained only 2.7% of NPC development in NPC high risk population. These findings should have important public health implications for NPC risk reduction in endemic regions.

The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.

Haplotype-dependent HLA susceptibility to nasopharyngeal carcinoma in a Southern Chinese population

We have conducted a comprehensive case–control study of a nasopharyngeal carcinoma (NPC) population cohort from Guangxi Province of Southern China, a region with one of the highest NPC incidences on record. A total of 1407 individuals including NPC patients, healthy controls, and their adult children were examined for the human leukocyte antigen (HLA) association, which is so far the largest NPC cohort reported for such studies. Stratified analysis performed in this study clearly demonstrated that while NPC protection is associated with independent HLA alleles, most NPC susceptibility is strictly associated with HLA haplotypes. Our study also detected for the first time that A*0206, a unique A2 subtype to South and Southeast Asia is also associated with a high risk for NPC. HLA-A*0206, HLA-B*3802 alleles plus the A*0207–B*4601 and A*3303–B*5801 haplotypes conferred high risk for NPC showing a combined odds ratio (OR) of 2.6 (P<0.0001). HLA alleles that associate with low risk for NPC include HLA-A*1101, B*27, and B*55 with a combined OR of 0.42 (P<0.0001). The overall high frequency of NPC-susceptible HLA factors in the Guangxi population is likely to have contributed to the high-NPC incidence in this region.

Genetic Polymorphisms of CYP2E1 , GSTP1 , NQO1 and MPO and the Risk of Nasopharyngeal Carcinoma in a Han Chinese Population of Southern China

BackgroundSouthern China is a major area for endemic nasopharyngeal carcinoma (NPC). Genetic factors as well as environmental factors play a role in development of NPC. To investigate the roles of previously described carcinogen metabolism gene variants for NPC susceptibility in a Han Chinese population, we conducted a case-control study in two independent study population groups afflicted with NPC in Guangdong and Guangxi Provinces of southern China.MethodsFive single nucleotide polymorphisms (SNPs) of CYP2E1-rs2031920, CYP2E1-rs6413432, GSTP1-rs947894, MPO-rs2333227 and NQO1-rs1800566 were genotyped by PCR-based RFLP, sequencing and TaqMan assay in 358 NPC cases and 629 controls (phase I cohort). Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI). To confirm our results, sixteen tag SNPs for GSTP1, MPO, NQO1 (which 100% covered these genes), and 4 functional SNPs of CYP2E1 were genotyped in another cohort of 213 NPC cases and 230 controls (phase II cohort).ResultsNo significant associations in NPC risk were observed for the five polymorphisms tested in the phase I cohort. In an additional stratified analysis for phase I, there was no significant association between cases and controls in NPC high risk population (EBV/IgA/VCA positive population). Analysis of 14 tagging SNPs within the same genes in an independent phase II cohort were in agreement with no SNPs significantly associated with NPC.ConclusionsOur results suggest that polymorphism of CYP2E1, GSTP1, MPO and NQO1 genes does not contribute to overall NPC risk in a Han Chinese in southern China.

Genetic factors leading to chronic Epstein-Barr virus infection and nasopharyngeal carcinoma in South East China: Study design, methods and feasibility

Nasopharyngeal carcinoma (NPC) is a complex disease caused by a combination of Epstein-Barr virus chronic infection, the environment and host genes in a multi-step process of carcinogenesis. The identity of genetic factors involved in the development of chronic Epstein-Barr virus infection and NPC remains elusive, however. Here, we describe a two-phase, population-based, case-control study of Han Chinese from Guangxi province, where the NPC incidence rate rises to a high of 25-50 per 100,000 individuals. Phase I, powered to detect single gene associations, enrolled 984 subjects to determine feasibility, to develop infrastructure and logistics and to determine error rates in sample handling. A microsatellite screen of Phase I study participants, genotyped for 319 alleles from 34 microsatellites spanning an 18-megabase region of chromosome 4 (4p15.1-q12), previously implicated by a linkage analysis of familial NPC, found 14 alleles marginally associated with developing NPC or chronic immunoglobulin A production (p = 0.001-0.03). These associations lost significance after applying a correction for multiple tests. Although the present results await confirmation, the Phase II study population has tripled patient enrolment and has included environmental covariates, offering the potential to validate this and other genomic regions that influence the onset of NPC.

Diagnostic significance of combined detection of Epstein-Barr virus antibodies, VCA/IgA, EA/IgA, Rta/IgG and EBNA1/IgA for nasopharyngeal carcinoma.

The objective of this study was to investigate the diagnostic significance of EBV antibody combined detection for nasopharyngeal carcinoma (NPC) in a high incidence region of southern China. Two hundred and eleven untreated NPC patients, 203 non-NPC ENT patients, and 210 healthy controls were recruited for the study. The titers of VCA/IgA and EA/IgA were assessed by immunoenzyme assay, and the levels of Rta/IgG and EBNA1/IgA were determined by enzyme-linked immunosorbent assay. The levels of VCA/IgA, EA/IgA, Rta/IgG and EBNA1/ IgA demonstrated no association with gender or age (p>0.05). The receiver operating characteristic curve and the area under the curve were used to evaluate the diagnostic value. The sensitivity of VCA/IgA (98.1%) and the specificity of EA/IgA (98.5%) were the highest. When a logistic regression model was used to combine the results from multiple antibodies to increase the accuracy, the combination of VCA/IgA+Rta/IgG, whose area under the curve was 0.99, had the highest diagnostic efficiency, and its sensitivity, specificity and Youden index were 94.8%, 98.0% and 0.93 respectively. The data suggest that the combination of VCA/IgA+Rta/IgG may be most suitable for NPC serodiagnosis.

Oral hygiene and risk of nasopharyngeal carcinoma - a population-based case-control study in China

Background: The association between oral health and risk of nasopharyngeal carcinoma (NPC) is largely unknown. Further understanding could shed light on potential pathogenic mechanisms and preventive measures. Methods: We conducted a population-based case–control study in southern China between 2010 and 2014. We enrolled 2,528 incident NPC cases, aged 20–74 years, and 2,596 controls, randomly selected from the total population registers, with frequency matching to the 5-year age and sex distribution of the cases by geographic region. We interviewed subjects using a structured questionnaire inquiring about oral health indicators and potential confounding factors. We used unconditional logistic regression to estimate multivariate-adjusted ORs with 95% confidence intervals (CI). Results: A higher number of filled teeth was associated with an elevated risk of NPC. Individuals with 1 to 3 and more than 3 teeth filled versus none had adjusted ORs of 1.25 (95% CI, 1.06–1.49) and 1.55 (95% CI, 1.13–2.12), respectively (Ptrend = 0.002). Conversely, the adjusted OR for those who brushed teeth twice or more per day versus once or less per day was 0.62 (95% CI, 0.55–0.70). We detected a borderline significant positive association with earlier age at first adult tooth loss. Conclusion: Our study suggested a positive association between some indicators of poor oral health and risk of NPC. Further studies are needed to confirm whether the findings are causal and, if so, to further explain the underlying mechanisms. Impact: Improvement of oral hygiene might contribute to reducing NPC risk. Cancer Epidemiol Biomarkers Prev; 25(8); 1201–7. ©2016 AACR.

Increased Serum Levels of Macrophage Inflammatory Protein-3α and Cystatin A Predict a Poor Prognosis of Nasopharyngeal Carcinoma

AbstractThis study was aimed to investigate the roles of serum macrophage inflammatory protein-3&agr; (MIP-3&agr;) and cystatin A in nasopharyngeal carcinoma (NPC) prognosis.The serum levels of MIP-3&agr; and cystatin A in 140 primary NPC patients without distant metastasis were detected by enzyme-linked immunosorbent assay before and after treatment. The results were compared with those in 100 healthy controls. The log-rank test was used to compare survival curves of the 2 groups. Multivariate analysis of prognostic factors used Cox proportional hazards regression model.Serum levels of MIP-3&agr; and cystatin A in pretreatment patients with NPC were higher than those in healthy controls. Concentrations of these 2 factors in the majority of patients after the therapy decreased to control level. Patients with high serum level of MIP-3&agr; and cystatin A before treatment had poorer overall survival (OS), local recurrence-free survival, and distant metastasis-free survival than the ones with low level. In addition, serum pretreatment MIP-3&agr; and cystatin A levels were independent prognostic factors for OS and distant metastasis-free survival of NPC patients; serum posttreatment MIP-3&agr; and cystatin A levels were independent prognostic factors of local recurrence-free survival.Our results revealed that serum MIP-3&agr; and cystatin A may be promising candidate prognostic factors for NPC, and higher serum levels of MIP-3&agr; and cystatin A correlate with shorter probability of OS, local recurrence, and distant metastasis.

Expression and Prognostic Significance of Macrophage Inflammatory Protein-3 Alpha and Cystatin A in Nasopharyngeal Carcinoma.

This study aims to investigate the expression of macrophage inflammatory protein-3 alpha (MIP-3α) and cystatin A in nasopharyngeal carcinoma (NPC) and their association with clinical characteristics and prognosis. Primary tumor specimens from 114 NPC patients and associated clinical follow-up data were collected, and the expression of MIP-3α and cystatin A proteins was investigated by immunohistochemistry. Expression of MIP-3α was significantly associated with TNM stage in patients with NPC (P < 0.05). NPC patients with positive expression of MIP-3α exhibited shorter median overall survival (OS) and distant metastasis-free survival (DMFS), compared with patients with negative expression (OS: 50.5 months versus 59.0 months, P = 0.013; DMFS: 50.1 months versus 60.2 months, P = 0.003). NPC patients with positive expression of cystatin A exhibited shorter median OS, local recurrence-free survival (LRFS), and DMFS, compared with patients with negative expression (OS: 51.1 months versus 60.0 months, P = 0.004; LRFS: 54.5 months versus 59.5 months, P = 0.036; DMFS: 52.3 months versus 58.8 months, P = 0.036). Both MIP-3α and cystatin A overexpressions in NPC tumor tissues were strong independent factors of poor prognosis in NPC patients. MIP-3α and cystatin A expressions may be valuable prognostic markers in NPC patients.

Prognostic Significance of Neutrophil to Lymphocyte Ratio, Lymphocyte to Monocyte Ratio, and Platelet to Lymphocyte Ratio in Patients with Nasopharyngeal Carcinoma

The peripheral blood neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) have been reported to correlate with the prognosis of many malignancies. This study evaluated the prognostic value of pretreatment NLR, LMR, and PLR in nasopharyngeal carcinoma (NPC). A retrospective analysis of clinical and pathological data of 140 NPC patients without distant metastasis during initial treatment was conducted to identify correlations between NLR, LMR, and PLR and clinicopathological features, overall survival, and progression-free survival. Cox proportional hazard regression analysis was used to reveal the independent factors affecting the prognosis of NPC patients. NLR was associated with T staging, N staging, and overall clinical stage grouping of the NPC patients (P < 0.05). NLR ≥ 2.28, LMR < 2.26, and PLR ≥ 174 were significantly associated with a relatively short overall survival (P < 0.05). In addition, NLR ≥ 2.28 was significantly associated with a relatively short progression-free survival (P < 0.05). Cox proportional hazard regression analysis showed that NLR was an independent prognostic factor in NPC. Pretreatment NLR, LMR, and PLR might be a useful complement to TNM staging in the prognostic assessment of NPC patients.