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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: In this large studied North African population, our findings suggest that the functional CYP2E1, CYP2A6, GSTM1 and GSTT1 variations did not influence NPC susceptibility.

Krüppel-like factor 4: A new potential biomarker of lung cancer.

Lung cancer is most prevalent human cancer worldwide. However, no molecular markers are currently available for predicting lung cancer prognosis. Therefore, identifying novel biomarkers may be useful for improving clinical diagnosis and patient stratification. Krüppel-like factor 4 (KLF4) is a transcription factor with opposing roles in different human cancers. Its overexpression in several cancers is correlated with a poor prognosis. However, the expression and role of KLF4 in lung cancer remains to be elucidated. The aim of this study was to determine the profile of KLF4 expression in different types of lung cancer. The KLF4 protein expression level was tested and evaluated by immunohistochemical analysis in 47 lung tumors and normal tissues, and then correlated with clinical characteristics. A differential expression of KLF4 was observed between normal tissue and each of the lung cancer types. A significant decrease in KLF4 expression was observed in non-small-cell lung cancer (NSCLC) compared with that in normal tissue, while significant overexpression was detected in small-cell lung cancer. Furthermore, a higher rate of expression was observed in stage II, III and IV disease compared with stage I disease in NSCLC tissues. KLF4 expression was not found to be associated with age or gender. Our results suggested that the KLF4 protein level may be a potential biomarker in patients with advanced lung cancer.

XRCC1 and hOGG1 genes and risk of nasopharyngeal carcinoma in North African countries.

Although genetic susceptibility to nasopharyngeal carcinoma (NPC) has been recognized for a long time, little is known about the responsible genes. X-Ray repair cross-complementing protein 1 (XRCC1) and human 8-oxo-guanine glycosylase 1 (hOGG1) genes are involved in deoxyribonucleic acid (DNA) repair and were found associated with NPC risk in three Asian case-control studies. The objective of the present study was to test these genes in a sample from North Africa, one of the major NPC endemic regions in the world. Three single nucleotide polymorphisms (SNPs) in the XRCC1 gene and one SNP in the hOGG1 gene were genotyped in 598 NPC cases from Morocco, Algeria, and Tunisia and 545 controls frequency matched by recruitment center, age, sex, and urban/rural household. The genotype and allelic distributions for the hOGG1 (326)Ser/Cys SNP and for the XRCC1 (399)Arg/Trp, (280)Arg/His, and (194)Arg/Trp SNPs did not differ significantly among NPC cases and controls. The XRCC1 (194)Trp allele frequency was significantly lower in the North African population than in Asian population (f = 0.04 vs. 0.31 in Cantonese Chinese and 0.21 Han Chinese). The hOGG1 (326)Ser allele frequency was significantly higher in the North African population (f = 0.73) than in Asian populations (f = 0.39 in Taiwanese). The results of the present study obtained from a large sample indicate that the XRCC1 and hOGG1 genes are unlikely to play a role in the susceptibility to NPC in North Africans. Our results do not corroborate those found in Asian population on smaller samples.

Dietary risk factors for nasopharyngeal carcinoma in Maghrebian countries.

North Africa is one of the major Nasopharyngeal Carcinoma (NPC) endemic regions. Specific food items unique to this area were implicated to be associated with NPC risk, but results were inconsistent. Here we have performed a large-scale case-control study in the Maghrebian population from Tunisia, Algeria and Morocco. From 2002 to 2005, interviews were conducted on 636 cases and 615 controls. Controls were hospitalized individuals from 15 non-cancer hospital departments, or friends and family members of non-NPC cancer subjects, matched by center, childhood household type (rural or urban), age and sex. Conditional logistic regression is used to evaluate the risk of factors. In results, consumption of rancid butter, rancid sheep fat and preserved meat not spicy (mainly quaddid) were associated with significantly increased risk of NPC, while consumption of cooked vegetables and industrial preserved fish was associated with reduced risk. Other foods such as fresh citrus fruits and spicy preserved meat (mainly osban) in childhood, industrial made olive condiments in adulthood, were marginally associated. In multivariate analyses, only rancid butter, rancid sheep fat and cooked vegetables were significantly associated with NPC. In regard to possible causative substances, our results implicate the involvement of butyric acid, a potential Epstein-Barr virus (EBV) activator.

Matrix metalloproteinase-1 (-1607) 1G/2G and -9 (-1562) C/T promoter polymorphisms: susceptibility and prognostic implications in nasopharyngeal carcinomas.

BACKGROUND: Matrix metalloproteinases (MMPs) are proteolytic enzymes that play important roles in tumor invasion and metastasis by degrading extracellular matrix components. Genetic variations in promoter regions of MMP genes, affecting their expression, have been associated with susceptibility to cancers. The aim of this study was to investigate the susceptibility and prognostic implications of the MMP-1 (-1607) 1G/2G and MMP-9 (-1562) C/T polymorphisms in nasopharyngeal carcinomas. METHODS: The variation of the MMP-1 and MMP-9 promoter regions in 174 patients with NPC and 171 healthy control subjects was investigated. Association of the clinico-pathologic parameters and the genetic markers with the rates of the nasopharyngeal carcinoma-specific overall survival and the disease-free survival were assessed using univariate and multivariate analyses. RESULTS: No association was found between genetic variation in MMP-9 and the risk of NPC occurrence. In contrast, a significantly increased risk of NPC was associated with the homozygous MMP-1 (-1607) 2G2G genotype (OR=2.27; p=0.02). A significant association was also found between the 2G2G genotype and the aggressive forms of NPC as defined by large tumor size (T3-T4), lymph node metastasis and advanced stages (III-IV) at the time of diagnosis. Moreover, an association was ascertained between the MMP-1 polymorphism and gender (OR=2.90; p=0.02). In univariate analysis, the MMP-1 (-1607) 2G allele showed a significant association with reduced disease-free survival for NPC patients (p=0.03). CONCLUSIONS: The genetic variation in MMP-1 may represent a marker for the increased risk of nasopharyngeal carcinoma.

TAP1 gene polymorphisms and nasopharyngeal carcinoma risk in a Tunisian population.

To find out whether polymorphisms 333-Ile/Val and 637-Asp/Gly of the transporter part of the antigen processing 1 gene (TAP1) are associated with the development of nasopharyngeal carcinoma (NPC), we studied a total of 374 subjects (209 patients and 165 controls). We used the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) method for analyzing the TAP1 gene polymorphisms. We found a significant difference between the patients and the controls in both the TAP1 codon 333 and codon 637 (P = 0.009 and P = 0.002, respectively). We also found that genotypes with the A allele were present in 206 patients with NPC and 155 controls (98.5 vs. 93.9%; P = 0.032; OR = 4.43) and that genotypes with the B allele were more often present in the control group (45 vs. 32%; P = 0.004; OR = 0.48), suggesting a significant positive association of the A allele with NPC risk and a protective role of the B allele. We have observed an association between the distribution of TAP1 alleles and the NPC patient's age at onset, compared with controls. These results back up the fact that the etiology of NPC in intermediate-risk countries is completely different in each peak of age prevalence and that each peak may possess its own particular oncogenic mechanism.

A polymorphism in FAS gene promoter associated with increased risk of nasopharyngeal carcinoma and correlated with anti-nuclear autoantibodies induction.

Loss of FAS (CD95) expression is a common feature of malignant transformation, which has been related to loss of epithelial cell differentiation and loss of sensitivity to apoptosis. We investigated the potential association between FAS promoter polymorphism and the genetic susceptibility to the Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma. The in vivo functional significance of the FAS polymorphism was investigated by assessing the correlation between FAS genotypes and the presence of autoantibodies to cytoskeleton and nuclear antigens frequently detected in nasopharyngeal carcinoma. We determined the FAS polymorphism distributions by RFLP-PCR in 170 patients with nasopharyngeal carcinoma and in 224 sex and age-matched controls. We used ELISA and the immunofluorescence analysis to characterize the presence of IgG autoantibodies to the cytoskeleton and nuclear proteins in patients' sera. A significantly increased risk of nasopharyngeal carcinoma was associated with heterozygote FAS-A/G (OR=2.00, P=0.001) and homozygote FAS-G/G (OR=3.19, P=0.0001) variants. The increased frequency of FAS-G/G genotype is correlated with the presence of anti-nuclear autoantibodies in patients with nasopharyngeal carcinoma (P=0.0298). Our results demonstrated that FAS promoter polymorphism was significantly associated with the nasopharyngeal carcinoma in Tunisians. The anti-nuclear autoantibodies induction was also found to be related to FAS polymorphism. The FAS promoter polymorphism associated not only with the increased risk of nasopharyngeal carcinoma in Tunisians but also with immune response deregulation observed in this cancer.

Polymorphism of the stress protein HSP70-2 gene is associated with the susceptibility to the nasopharyngeal carcinoma.

Several studies have shown statistical evidence of association between nasopharyngeal carcinoma (NPC) and specific human leukocyte antigen (HLA) alleles and highlighted the presence of candidate genes for this cancer within or nearby the HLA. Given their chromosomal location within HLA and their determining role in the immune response to tumor cells, we designed a case-controlled study to investigate the potential association of the genetic variation of the tumor necrosis factor-alpha (TNF-alpha) and that of the heat shock protein 70-2 (HSP70-2) with NPC. We used the polymerase chain reaction and restriction enzyme digestion to characterize the variation of the TNF-alpha promoter region and that of the HSP70-2 gene in 140 Tunisian patients with primary NPC and 274 healthy control subjects. No association was found between genetic variations in TNF-alpha and the risk of NPC in Tunisians. In contrast, a significant relative risk of NPC was found associated with the HSP70-2 homozygous genotype (P2/P2) (OR=2.309; P=0.006). The P2/P2 genotype of the HSP70-2 gene may be a marker of increased risk of NPC in Tunisians.

Autoantibodies to tubulin are specifically associated with the young age onset of the nasopharyngeal carcinoma.

By far the highest incidence of the Epstein-Barr virus (EBV)-associated nasopharyngeal carcinomas in young subjects was found in North Africa, a region of intermediate risk for adults. We used the immunofluorescence analysis and ELISA to characterize the presence of IgG autoantibodies to the cytoskeleton and nuclear proteins in sera of 82 Tunisian patients with primary nasopharyngeal carcinoma and those of 82 healthy subjects. To assess the specificity of the sera autoreactivity, inhibition tests were carried out using free autoantigens. Analysis of sera autoreactivity in patients with nasopharyngeal carcinoma and in control subjects showed that 23% of the patients had serum reactivity against more than 1 autoantigen tested compared to 1.2% in the control group (p = 10(-4)). The most frequent auto reactivity in patient's sera was found with tubulin and nuclear proteins (19.5% and 22% respectively vs. 6.1% and 1.2% in controls). The IgG auto reactivity inhibition studies indicate that all autoantigens, except native DNA, showed low values of IC(50) (concentration of antigen causing 50% inhibition of the antibody binding) reflecting the high affinity of these IgG autoantibodies. When patients and controls were stratified according to their age, IgG autoantibodies to tubulin were found specifically associated with the young age onset of the nasopharyngeal carcinoma (age under 25 years). IgG auto reactivity comparison before and after cancer therapy showed that only anti-tubulin reactivity was significantly affected by treatment. Our results demonstrate that the autoantibodies to the cytoskeleton and nuclear proteins are associated with the nasopharyngeal carcinoma in Tunisians. The anti-tubulin IgG autoantibodies may represent a serologic marker for the nasopharyngeal carcinoma in children and adolescents Tunisians.