Hai De Qin

Traditional Cantonese diet and nasopharyngeal carcinoma risk: A large-scale case-control study in Guangdong, China

BackgroundNasopharyngeal carcinoma (NPC) is rare in most parts of the world but is a common malignancy in southern China, especially in Guangdong. Dietary habit is regarded as an important modifier of NPC risk in several endemic areas and may partially explain the geographic distribution of NPC incidence. In China, rapid economic development during the past few decades has changed the predominant lifestyle and dietary habits of the Chinese considerably, requiring a reassessment of diet and its potential influence on NPC risk in this NPC-endemic area.MethodsTo evaluate the association between dietary factors and NPC risk in Guangdong, China, a large-scale, hospital-based case-control study was conducted. 1387 eligible cases and 1459 frequency matched controls were recruited. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated using a logistic regression model, adjusting for age, sex, education, dialect, and habitation household type.ResultsObservations made include the following: 1) consumption of canton-style salted fish, preserved vegetables and preserved/cured meat were significantly associated with increased risk of NPC, with enhanced odds ratios (OR) of 2.45 (95% CI: 2.03-2.94), 3.17(95% CI: 2.68-3.77) and 2.09 (95% CI: 1.22-3.60) respectively in the highest intake frequency stratum during childhood; 2) consumption of fresh fruit was associated with reduced risk with a dose-dependent relationship (p = 0.001); and 3) consumption of Canton-style herbal tea and herbal slow-cooked soup was associated with decreased risk, with ORs of 0.84 (95% CI: 0.68-1.03) and 0.58 (95% CI: 0.47-0.72) respectively in the highest intake frequency stratum. In multivariate analyses, these associations remained significant.ConclusionsIt can be inferred that previously established dietary risk factors in the Cantonese population are still stable and have contributed to the incidence of NPC.

Sequence Variants in Toll-Like Receptor 10 Are Associated with Nasopharyngeal Carcinoma Risk

Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. Genetic susceptibility is a major factor in determining the individual risk of NPC in these areas. To test the association between NPC and variants in Toll-like receptor 10 (TLR10), we conducted a hospital-based case-control study in a Cantonese-speaking population in Guangdong province. Seven single nucleotide polymorphisms in TLR10, selected with a tagging algorithm, were genotyped. When assessing each unique haplotype compared with the most common haplotype, “GAGTGAA,” with the expectation-maximization algorithm in Haplo.stats, the risk of developing NPC was significantly elevated among men who carried the haplotype “GCGTGGC” (P = 0.005). After adjusting for age, gender, and VCA-IgA antibody titers, this association was more significant (P = 0.0007). To further assess the overall differences of haplotype frequency profiles between cases and healthy controls, the global score test, considering all haplotypes and adjusting for age, gender, and VCA-IgA antibody titers, gave a haplo score of 27.52 with P = 0.002. The haplotype specific odds ratio was 2.66 (confidence interval, 1.34-3.82) for GCGTGGC. We concluded that in this Cantonese population–based study, haplotype GCGTGGC with frequency of 11.4% in TLR10 was found to be associated with NPC and this association was statistically significant after adjusting for age, gender, and VCA-IgA antibody titers. It is possible that this is not a causal haplotype for NPC; rather, it is in strong linkage disequilibrium with a causal single nucleotide polymorphism in close proximity. (Cancer Epidemiol Biomarkers Prev 2006;15(5):862–6)

Centromere Protein H Is a Novel Prognostic Marker for Nasopharyngeal Carcinoma Progression and Overall Patient Survival

Purpose: The aim of the present study was to analyze the expression of Centromere protein H (CENP-H), one of the fundamental components of the human active kinetochore, in nasopharyngeal carcinoma (NPC) and to correlate it with clinicopathologic data, including patient survival. Experimental Design: Using reverse transcription-PCR and Western blot, we detected the expression of CENP-H in normal nasopharyngeal epithelial cells, immortalized nasopharyngeal epithelial cell lines, and NPC cell lines. Using immunohistochemistry, we analyzed CENP-H protein expression in 160 clinicopathologically characterized NPC cases. Statistical analyses were applied to test for prognostic and diagnostic associations. Results: Reverse transcription-PCR and Western blot showed that the expression level of CENP-H was higher in NPC cell lines and in immortalized nasopharyngeal epithelial cells than in the normal nasopharyngeal epithelial cell line at both transcriptional and translational levels. By immunohistochemical analysis, we found that 76 of 160 (47.5%) paraffin-embedded archival NPC biopsies showed high expression of CENP-H. Statistical analysis showed that there was a significant difference of CENP-H expression in patients categorized according to clinical stage (P = 0.024) and T classification (P = 0.027). Patients with higher CENP-H expression had shorter overall survival time, whereas patients with lower CENP-H expression had better survival. A prognostic value of CENP-H was also found of the subgroup of N0-N1 tumor classification. Multivariate analysis showed that CENP-H expression was an independent prognostic indicator for patients survival. Conclusions: Our results suggest that CENP-H protein is a valuable marker of NPC progression. High CENP-H expression is associated with poor overall survival in NPC patients.

Effect of family history of cancers and environmental factors on risk of nasopharyngeal carcinoma in Guangdong, China.

BACKGROUND Family history of nasopharyngeal carcinoma (NPC) is an established risk factor for this cancer, but the contributions of family history of other types of cancer and its interaction with environmental factors have not been well characterized. METHODS A total of 1845 incident cases of NPC and 2275 matched controls from Guangdong, China were included in this study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models adjusted for smoking, consumption of alcohol, salted fish consumption, and demographic factors. RESULTS A significant association between the risk of NPC and family history of any cancers in first degree relatives was observed, and higher number of affected family member was related to a higher risk (P(trend)<0.01). Family history of NPC was the strongest predictor for NPC (OR: 3.35, 95% CI: 2.46-4.55 for all first degree relatives). The risk of NPC was also positively associated with history of head and neck cancer among parents and lung and breast cancers among siblings. The combination of family history of cancer, especially NPC, and the consumption of salt-preserved fish significantly increased the risk for NPC. CONCLUSIONS These results confirm that the risk for NPC increases with family history of NPC and suggest that lung and breast cancer contribute to risk for NPC. A possible interaction between family history of cancer, especially NPC, and consumption of salt-preserved fish in the development of NPC was also identified.

A Case–control and a family-based association study revealing an association between CYP2E1 polymorphisms and nasopharyngeal carcinoma risk in Cantonese

Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but is more prevalent in Southern China, especially in Guangdong. The cytochrome P450 2E1 (CYP2E1) has been recognized as one of the critically important enzymes involved in oxidizing carcinogens and is probably to be associated with NPC carcinogenesis. To systematically investigate the association between genetic variants in CYP2E1 and NPC risk in Cantonese, two independent studies, a family-based association study and a case-control study, were conducted using the haplotype-tagging single-nucleotide polymorphism approach. A total of 2499 individuals from 546 nuclear families were initially genotyped for the family-based association study. Single-nucleotide polymorphisms (SNPs) rs9418990, rs915908, rs8192780, rs1536826, rs3827688 and one haplotype h2 (CGTGTTAA) were revealed to be significantly associated with the NPC phenotype (P = 0.045-0.003 and P = 0.003, respectively). To follow up the initial study, a case-control study including 755 cases and 755 controls was conducted. Similar results were observed in the case-control study in individuals <46 years of age and had a history of cigarette smoking, with odds ratios (ORs) of specific genotypes ranging from 1.88 to 2.99 corresponding to SNP rs9418990, rs3813865, rs915906, rs2249695, rs8192780, rs1536826, rs3827688 and of haplotypes h2 with OR = 1.65 (P = 0.026), h5 (CCCGTTAA) with OR = 2.58 (P = 0.007). The values of false-positive report probability were <0.015 for six SNPs, suggesting that the reported associations are less probably to be false. This study provides robust evidence for associations between genetic variants of CYP2E1 and NPC risk.

Comprehensive pathway-based association study of DNA repair gene variants and the risk of nasopharyngeal carcinoma.

DNA repair plays a central role in protecting against environmental carcinogenesis, and genetic variants of DNA repair genes have been reported to be associated with several human malignancies. To assess whether DNA gene variants were associated with nasopharyngeal carcinoma (NPC) risk, a candidate gene association study was conducted among the Cantonese population within the Guangdong Province, China, the ethnic group with the highest risk for NPC. A 2-stage study design was utilized. In the discovery stage, 676 tagging SNPs covering 88 DNA repair genes were genotyped in a matched case-control study (cases/controls = 755/755). Eleven SNPs with P(trend) < 0.01 were identified. Seven of these SNPs were located within 3 genes, RAD51L1, BRCA2, and TP53BP1. In the validation stage, these 11 SNPs were genotyped in a separate Cantonese population (cases/controls = 1,568/1,297). Two of the SNPs (rs927220 and rs11158728), both in RAD51L1, remained strongly associated with NPC. The SNP rs927220 had a significant P(combined) of 5.55 × 10(-5), with OR = 1.20 (95% CI = 1.10-1.30), Bonferroni corrected P = 0.0381. The other SNP (rs11158728), which is in strong linkage disequilibrium with rs927220 (r(2) = 0.7), had a significant P(combined) of 2.0 × 10(-4), Bonferroni corrected P = 0.1372. Gene-environment interaction analysis suggested that the exposures of salted fish consumption and cigarette smoking had potential interactions with DNA repair gene variations, but need to be further investigated. Our findings support the notion that DNA repair genes, in particular RAD51L1, play a role in NPC etiology and development.

Haplotype of gene Nedd4 binding protein 2 associated with sporadic nasopharyngeal carcinoma in the Southern Chinese population

BackgroundBcl-3 as an oncoprotein is overexpressed in nasopharyngeal carcinoma (NPC). Nedd4 binding protein 2 (N4BP2), which is located in the NPC susceptibility locus, is a Bcl-3 binding protein. This study is aimed to explore the association between N4BP2 genetic polymorphism and the risk of NPC.MethodsWe performed a hospital-based case-control study, including 531 sporadic NPC and 480 cancer-free control subjects from southern China. PCR-sequencing was carried out on Exons, promoter region and nearby introns of the N4BP2 gene. The expression pattern of N4BP2 and Bcl-3 was also analyzed.ResultsWe observed a statistically significant difference in haplotype blocks ATTA and GTTG between cases and controls. In addition, three novel SNPs were identified, two of which were in exons (loc123-e3l-snp2, position 39868005, A/G, Met171Val; RS17511668-SNP2, position 39926432, G/A, Glu118Lys), and one was in the intron6 (RS794001-SNP1, position 39944127, T/G). Moreover, N4BP2 was at higher levels in a majority of tumor tissues examined, relative to paired normal tissues.ConclusionThese data suggest that haplotype blocks ATTA and GTTG of N4BP2 is correlation with the risk of sporadic nasopharyngeal carcinoma in the Southern Chinese population and N4BP2 has a potential role in the development of NPC.

Human genetic variants of homologous recombination repair genes first found to be associated with Epstein–Barr virus antibody titers in healthy Cantonese†

Epstein–Barr virus (EBV) infection is a major risk factor for nasopharyngeal carcinoma (NPC). Despite high prevalence of infection among the general population worldwide, only a small proportion of infected individuals presents with seropositivity for EBV‐specific IgA antibodies. This seropositive subgroup of EBV carriers has an elevated cumulative risk for NPC during their lifetime. Previous studies reported that the host homologous recombination repair (HRR) system participates in EBV lytic replication, suggesting a potential mechanism to influence EBV reactivation status and thus seropositivity. To investigate whether genetic variants of HRR genes are associated with the serostatus in a healthy population, we investigated the association between seropositivity for anti‐VCA‐IgA and 156 tagging SNPs in 35 genes connected with HRR in an observational study among 755 healthy Cantonese speakers in southern China. Six variant alleles of MDC1, RAD54L, TP53BP1, RPA1, LIG3 and RFC1 exhibited associations with seropositivity (ptrend from 0.0085 to 0.00027). Our study provides evidence that genetic variation within the HRR might affect an individuals propensity for EBV seropositive status of anti‐VCA IgA antibody.

Genetic polymorphisms of CYP2A13 and its relationship to nasopharyngeal carcinoma in the Cantonese population

Nasopharyngeal carcinoma (NPC) is characterized by a high prevalence in Southern China, especially among Cantonese individuals of the Guangdong Province. Epidemiological studies have suggested that frequent exposure to high levels of nitrosamine from preserved foods such as salted fish could be a risk factor for NPC. Cytochrome P450 encompasses a family of enzymes that metabolize carcinogens and CYP2A13, a member of this family, is expressed predominantly in the respiratory tract with the highest levels in the nasal mucosa. In an effort to test whether a correlation exists between CYP2A13 genetic polymorphism and the risk of developing NPC, we sequenced all nine exons and the exon-intron junctions of the CYP2A13 gene in 45 NPC patients. We identified a total of 21 single nucleotide polymorphism (SNPs), including 7 novel SNPs. The most frequent functional variant allele was 74A-1757G-3375T-7233G with a haplotype frequency of 7.8% in the 45 NPC cases. In addition, a stop codon mutation was detected in one case. We then selected the 3 most frequent SNPs and one stop codon mutation to expand our study to a case-control analysis within the Cantonese population. A novel haplotype consisting 8 SNPs in introns, and four additional novel SNPs were identified; but no correlation between CYP2A13 genetic polymorphism and individual susceptibility to NPC was observed.

A Functional Variant in the Transcriptional Regulatory Region of Gene LOC344967 Cosegregates with Disease Phenotype in Familial Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma is a common malignancy in Southeast Asian countries, and genetic background is a well-known component of the complexity underlying its tumorigenic process. We have mapped a nasopharyngeal carcinoma susceptibility locus to chromosome 4p15.1-q12 in a previous linkage study on nasopharyngeal carcinoma pedigrees. In this study provided in this communication, we screened all the genes in this region, with a focus on exons, promoters, and the exon-intron boundary to identify nasopharyngeal carcinoma-associated mutations or functional variants. Importantly, we found a novel gene (LOC344967) with a single nucleotide polymorphism -32G/A in the promoter region. This gene is a member of the acyl CoA thioesterase family that plays an important role in fatty acid metabolism and is involved in the progression of various types of tumors. The -32A variant was found cosegregated with the disease phenotype in the nasopharyngeal carcinoma pedigrees that we previously used for the linkage study. Moreover, this -32A variant creates an activator protein (AP-1)-binding site in the transcriptional regulatory region of LOC344967, which significantly enhanced the binding of AP-1 to the promoter region and the transcription activity of the promoter in vivo. Furthermore, the expression of LOC344967 was significantly up-regulated at both mRNA and protein levels in nasopharyngeal carcinoma cells sharing the -32G/A genotype compared with nasopharyngeal carcinoma cells with the -32G/G genotype. Collectively, these results provide evidence that the -32A variant is a functional sequence change and may be related to nasopharyngeal carcinoma susceptibility in the families studied.