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ABSTRACT: AIM: The cell cycle checkpoint kinase 2 (CHK2) protein participates in the DNA damage response in many cell types. Germline mutations in CHK2 (1100delC, IVS2+1G>A and I157T) have been associated with a range of cancer types. This study aimed to investigate whether CHK2 1100delC, IVS2+1G>A and I157T mutations play an important role in the development of hepatocellular carcinoma (HCC) in Turkish population. METHODS: A total of 165 hepatocellular cancer cases and 446 cancer-free controls were genotyped for CHK2 mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-polymerase chain reaction (AS-PCR) methods. RESULTS: We did not find CHK2 1100delC, IVS2+1G>A and I157T mutations in any of 611 Turkish subjects. CONCLUSION: Our results demonstrate for the first time that CHK2 1100delC, IVS2+1G>A and I157T mutations have not been a genetic susceptibility factor for HCC in the Turkish population. Overall, our data suggests that genotyping of CHK2 mutations in clinical settings in the Turkish population should not be recommended. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.
Gene 10/2012; · 2.34 Impact Factor
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ABSTRACT: AIM: The programmed cell death-1 (PD-1) is a potent immunoregulatory molecule which is responsible for the negative regulation of T-cell activation and peripheral tolerance. Recently, overexpression of PD-1 has been reported to contribute to immune system evasion and poor survival of hepatocellular carcinoma (HCC). A common single nucleotide polymorphism in intron 4 of PD-1 gene called PD-1.3 has been reported to influence PD-1 expression, but its association with HCC has yet to be investigated. The aim of the present study was to investigate whether this polymorphism could be involved in the risk of HCC susceptibility. METHODS: The genotype frequency of PD-1.3 polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 236 subjects with HCC and 236 cancer-free control subjects matched on age, gender, smoking and alcohol status. RESULTS: No statistically significant differences were found in the genotype distributions of the PD-1.3 polymorphism among HCC and cancer-free control subjects (P=0.22). CONCLUSION: Our results demonstrate for the first time that the PD-1.3 polymorphism has not been in any major role in genetic susceptibility to hepatocellular carcinogenesis, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.
Gene 10/2012; · 2.34 Impact Factor
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ABSTRACT: The cell cycle checkpoint kinase 2 (CHEK2) protein participates in the DNA damage response in many cell types. Germline mutations in CHEK2 (1100delC, IVS2+1G>A and I157T) have been impaired serine/threonine kinase activity and associated with a range of cancer types. This hospital-based case-control study aimed to investigate whether CHEK2 1100delC, IVS2+1G>A and I157T mutations play an important role in the development of colorectal cancer (CRC) in Turkish population.
A total of 210 CRC cases and 446 cancer-free controls were genotyped for CHEK2 mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-polymerase chain reaction (AS-PCR) methods.
We did not find the CHEK2 1100delC, IVS2+1G>A and I157T mutations in any of the Turkish subjects.
Our result demonstrate for the first time that CHEK2 1100delC, IVS2+1G>A and I157T mutations have not been agenetic susceptibility factor for CRC in the Turkish population. Overall, our data suggest that genotyping of CHEK2 mutations in clinical settings in the Turkish population should not be recommended. However, independent studies are need to validate our findings in a larger series, as well as in patients of different ethnic origins.
Cancer epidemiology. 04/2012; 36(5):453-7.
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ABSTRACT: Exonuclease 1 (Exo 1) is an important nuclease involved in mismatch repair system that contributes to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. A guanine (G)/adenine (A) common single nucleotide polymorphism at first position of codon 589 in Exo 1 gene determines a glutamic acid (Glu, E) to lysine (Lys, K) (K589E) aminoacidic substitution which may alter cancer risk by influencing the activity of Exo 1 protein. Exo 1 K589E polymorphism has been studied in various cancers, but its association with hepatocellular carcinoma (HCC) has yet to be investigated. To determine the association of the Exo 1 K589E polymorphism with the risk of HCC development in a Turkish population, a hospital-based case-control study was designed consisting of 224 subjects with HCC and 224 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the Exo 1 K589E polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Our data shows that the Lys/Lys genotype of the Exo 1 K589E polymorphism is associated with increased risk of HCC development in this Turkish population [odds ratio (OR) = 2.15, 95% confidence interval (CI): 1.13-4.09, P = 0.02]. Furthermore, according to stratified analysis, a significant association was observed between the homozygote Lys/Lys genotype and HCC risk in the subgroups of male gender (OR = 2.67, 95% CI: 1.27-5.61, P = 0.009) and patients with non-viral-related HCC (OR = 3.14, 95% CI: 1.09-8.99, P = 0.03). Because our results suggest for the first time that the Lys/Lys homozygote genotype of Exo 1 K589E polymorphism may be a genetic susceptibility factor for HCC in the Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different ethnic origins.
Molecular Biology Reports 12/2011; 39(5):5943-51. · 2.93 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are an abundant class of small non-protein coding RNAs with posttranscriptional regulatory functions as tumor suppressors and oncogenes. Aberrant expression and structural alteration of miRNAs are considered to participate in tumorigenesis and cancer development. It has been suggested that the presence of single nucleotide polymorphisms in precursor miRNAs (pre-miRNAs) can alter miRNA processing, expression, and/or binding to target mRNA and represent another type of genetic variability that can contribute to the susceptibility of human cancers. A G/C polymorphism (rs2910164), which is located in the sequence of miR-146a precursor, results in a change from G:U to C:U in its stem region.
To determine the association of the miR-146a rs2910164 polymorphism on the risk of hepatocellular carcinoma (HCC) development in Turkish population, a hospital-based case-control study was designed consisting of 222 subjects with HCC and 222 cancer-free control subjects matched on age, gender, smoking and alcohol status. The genotype frequency of miR-146a rs2910164 polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.
No statistically significant differences were found in the allele or genotype distributions of the miR-146a rs2910164 polymorphism among HCC and cancer-free control subjects (p>0.05).
Our results demonstrate that the miR-146a rs2910164 polymorphism has no major role in genetic susceptibility to hepatocellular carcinogenesis, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.
Gene 10/2011; 486(1-2):104-9. · 2.34 Impact Factor
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ABSTRACT: The tumor suppressor p53 gene plays a crucial role in preventing carcinogenesis through its ability to induce cell cycle arrest and apoptosis following DNA damage and oncogene activation. A guanine (G)/cytosine (C) common single nucleotide polymorphism (SNP) at second position of codon 72 in exon 4 of p53 gene determines a arginine (Arg) to proline (Pro) (Arg72Pro) aminoacidic substitution within the proline-rich domain of p53 protein. Arg72 and Pro72 allele are different from a biochemical and biological point of view and many reports suggest that they can modulate individual cancer susceptibility. To determine the association of the p53 Arg72Pro polymorphism with the risk of hepatocellular carcinoma (HCC) development in a Turkish population, a hospital-based case-control study was designed consisting of 119 subjects with HCC and 119 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the p53 Arg72Pro polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Our data shows that the Pro/Pro genotype of the p53 Arg72Pro polymorphism is associated with increased risk of HCC development in this Turkish population (OR = 3.20, 95% CI: 1.24-8.22, P = 0.02). Furthermore, according to stratified analysis, a significant association was observed between the homozygote Pro/Pro genotype and HCC risk in the subgroups of male gender (OR = 3.01, 95% CI: 1.14-7.97, P = 0.03) and patients with hepatitis B virus (HBV)-related HCC (OR = 4.04, 95% CI: 1.46-11.15, P = 0.007). Because our results suggest for the first time that the Pro/Pro homozygote of p53 Arg72Pro polymorphism may be a genetic susceptibility factor for HCC (especially in the male gender and HBV-infected patients) in the Turkish population, further independent studies are required to validate our findings in a larger series, as well as in patients of different ethnic origins.
Molecular Biology Reports 05/2011; 39(2):1639-47. · 2.93 Impact Factor
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ABSTRACT: Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of apoptosis and cell cycle regulation. A common single nucleotide polymorphism (-31G>C) at the survivin promoter has been extensively studied in various cancers and reported to influence survivin expression, but its association with hepatocellular carinoma (HCC) has yet to be investigated. The aim of the present study was to investigate whether this polymorphism could be involved in the risk of HCC susceptibilty.
The genotype frequency of survivin -31G>C polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 160 subjects with HCC and 241 cancer-free control subjects matched on age, gender, smoking and alcohol status.
No statistically significant differences were found in the genotype distributions of the survivin -31G>C polymorphism among HCC and cancer-free control subjects (p=0.28).
Our results demonstrate for the first time that the survivin -31G/C polymorphism have not been any major role in genetic susceptibilty to hepatocellular carcinogenesis, at least in the population studied here.
Cancer epidemiology. 02/2011; 35(6):555-9.
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ABSTRACT: MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs with posttranscriptional regulatory functions as tumor suppressors and oncogenes. It has been suggested that the presence of single nucleotide polymorphisms (SNPs) in miRNAs can alter miRNA processing, expression, and/or binding to target mRNA and represent another type of genetic variability that can contribute to susceptibility to cancer development in humans. An adenine to guanine polymorphism (rs3746444), located in the sequence of miR-499, results in a change from A:U to G:U in its stem region. To determine the association of this polymorphism with the risk of hepatocellular carcinoma (HCC) in a Turkish population, a hospital-based case-control study was designed consisting of 222 subjects with HCC and 222 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the miR-499 rs3746444 polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. No statistically significant differences were found in the allele or genotype distributions of the miR-499 rs3746444 polymorphism among HCC and cancer-free control subjects (P>0.05). Our results demonstrate for the first time that the miR-499 rs3746444 polymorphism does not been any major role in genetic susceptibility to hepatocellular carcinogenesis, at least in the population studied here. Independent studies are need to validate our findings in a larger series, as well as in patients of different ethnic origins.
Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(11):3107-12. · 0.66 Impact Factor
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ABSTRACT: Cyclooxygenase-2 (COX-2) influences carcinogenesis through immune response suppression, apoptosis inhibition, regulation of angiogenesis and tumor cell invasion, and metastasis. It is now well established that COX-2 is overexpressed in many premalignant, malignant, and metastatic cancers, including hepatocellular carcinoma (HCC). DNA sequence variations in the COX-2 gene may lead to altered COX-2 production and/or activity, and so they cause inter-individual differences in the susceptibility to HCC. Functional coding region polymorphisms -1195A>G (rs689466), -765G>C (rs20417), and +8473T>C (rs5275) in the COX-2 gene have recently been shown to be associated with several human cancers but their association with HCC has yet to be investigated. We used hospital-based case-control study to assess the hypothesis that the functional COX-2 variation may affect individual susceptibility to the HCC. COX-2 polymorphisms were investigated in 129 confirmed subjects with HCC and 129 cancer-free control subjects matched on age, gender, smoking, and alcohol consumption using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The distribution of the COX-2 -1195A>G and +8473T>C genotypes were not significantly different between HCC cases and control. However, proportion of the COX-2 -765CC genotype which leads to a 30% reduction of the COX-2 promoter activity was significantly lower in patients with HCC (3.1%) when compared to control subjects (11.6%) (P < 0.05). Logistic regression analyses revealed that the COX-2 -765G>C variant genotype (-765CC) was associated with a significantly decreased risk of HCC compared with the -765GG wild-type homozygotes [P < 0.05, odds ratio (OR) = 0.25, 95% confidence interval (CI) = 0.08-0.79]. Our results suggest for the first time that the -765CC genotype of COX-2 -765G>C polymorphism, causing lower COX-2 gen expression, is a genetic protective factor for HCC. However, because this is the first report concerning the COX-2 -1195A>G, -765G>C, and +8473T>C polymorphisms and the risk of HCC, independent studies are needed to validate our findings.
Molecular and Cellular Biochemistry 11/2010; 347(1-2):201-8. · 2.06 Impact Factor
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ABSTRACT: The mouse double minute 2 (MDM2) gene represents one of the central nodes in the p53 pathway. A naturally occurring T/G single nucleotide polymorphism (SNP) in the intronic promoter of MDM2, SNP309 (rs2279744), was shown to influence MDM2 expression and p53 activity. SNP in the promoter region of MDM2 gene has recently been shown to be associated with accelerated tumor formation in both hereditary and sporadic cancers in humans. In this study, we aim to evaluate the association of SNP309 with the risk of hepatocellular carcinoma (HCC) development among Turkish population.
MDM2 SNP309 polymorphism was investigated in 110 confirmed subjects with HCC and 110 cancer-free control subjects matched on age, gender, smoking and alcohol consumption by using a polymerase chain reaction-restriction fragment length polymorphism assay.
The allele frequencies of case subjects (T, 0.48; G, 0.52) were significantly different from those of control subjects (T, 0.65; G, 0.35) (p=0.003). The proportion of GG genotype of the SNP309 in patients with HCC (26%) was significantly higher than that in patients without HCC (14%). We observed that compared with the TT genotype, the genotypes containing G allele [TG (OR, 2.19; 95% CI, 1.18-4.07; p=0.013) or GG (OR, 3.63; 95% CI, 1.65-8.00; p=0.001)] were associated with significant increased susceptibility to HCC.
Our findings suggest that the MDM2 promoter SNP309 G allele is associated with presence of HCC in Turkish population.
Cancer epidemiology. 05/2010; 34(4):448-52.
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ABSTRACT: A common G to A polymorphism (G870A) in the splice donor region of exon 4 of cyclin D1 (CCND1) gene generates two mRNAs (cyclin D1a and D1b) through an alternative splicing at the site of this polymorphism. Cyclin D1a and b proteins differ in their COOH-terminus, a region involved in protein degradation. We examined the association between this CCDN1 genotype and the susceptibility to hepatocellular carcinoma (HCC) in a Turkish population.
The genotype frequency of this polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Hospital-based case-control study was designed consisting of 160 diagnosis subjects with hepatocellular carcinoma and 160 cancer-free control subjects matched on age, gender, smoking and alcohol status.
The allele frequencies of case subjects (A, 0.55; G, 0.45) were significantly different from those of control subjects (A, 0.42; G, 0.58) (p=0.002). The odds ratios (ORs) for the CCND1 870 GA and AA genotypes when compared with the GG genotypes were 1.39 (95% confidence interval [CI] 0.82-2.36, p=0.22) and 2.52 (95% CI 1.38-4.62, p=0.003) respectively. The presence of at least one CCND1 870A allele was associated with increased risk for HCC (OR, 1.73; 95% CI, 1.06-2.82, p=0.03). When combining the GG and GA genotypes as a reference genotype, we found that the OR for the AA genotype was 2.06 (95% CI 1.24-3.44, p=0.006).
Our results suggest that the CCND1 G870A single nucleotide polymorphism is associated with an increased risk of HCC in our Turkish population.
Cancer epidemiology. 03/2010; 34(3):298-302.
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ABSTRACT: Proton pump inhibitors are mainly metabolized by cytochrome P450 2C19 in the liver. Recently, some studies have shown that the acid suppressing effect of proton pump inhibitors are influenced by a functional polymorphism of cytochrome P450 2C19. The aim of the present study was to investigate the effect of cytochrome P450 2C19 polymorphism on Helicobacter pylori eradication in patients who received proton pump inhibitors based triple therapy.
We determined the incidence of cytochrome P450 2C19 genotypes and the effect of cytochrome P450 2C19 genotypes on Helicobacter pylori eradication rates in 105 patients with Helicobacter pylori-positive chronic gastritis. Upper endoscopic procedure and gastric biopsies were performed in all patients. Helicobacter pylori was demonstrated histologically. Lansoprazole, amoxicillin and clarithromycin twice a day for 14 days were prescribed for those found to be infected with Helicobacter pylori. More than one month after the medication, a 13C urea breath test was conducted to examine the success or failure of the eradication treatment. Cytochrome P450 2C19 polymorphism was analyzed by the polymerase chain reaction-restriction fragment length polymorphism method.
The genotypes of cytochrome P450 2C19 were classified into the three groups, as rapid extensive metabolizer, intermediate metabolizer and poor metabolizer. In our patient population, the frequencies of rapid extensive metabolizer, intermediate metabolizer and poor metabolizer were 72%, 23% and 5%, respectively. The eradication rate was 70.0% for rapid extensive metabolizer, 92% for intermediate metabolizer and 80% for poor metabolizer. The eradication rate was highest in intermediate metabolizer patients.
The present study confirmed the low eradication rate for rapid extensive metabolizer. Our findings provide evidence that the cytochrome P450 2C19 genotype is useful to predict the success of treatment. For the rapid extensive metabolizer group, alternative regimens can be tried to increase the Helicobacter pylori eradication rates.
The Turkish journal of gastroenterology: the official journal of Turkish Society of Gastroenterology 03/2010; 21(1):23-8. · 0.47 Impact Factor
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ABSTRACT: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a cytosolic enzyme that catalyzes the two-electron reduction of numerous quinoid compounds into their less toxic form, thus NQO1 protecting cells against oxidative stress. The gene coding for NQO1 has a single nucleotide polymorphism (C-->T) at nucleotide position 609 (proline to serine substitution at position 187 in amino acid sequence (P187S)) (rs1800566) of the NQO1 cDNA which results in very low enzimatic activity, so it would be expected that individuals with the homologous NQO1 C609T polymorphism would have a susceptibility developing cancer. Previous studies of the association between functional NQO1 C609T polymorphism and several human cancers have had mixed findings but association of NQO1 C609T polymorphism with hepatocellular carcinoma (HCC) development has yet to be investigated. In this study, we aim to evaluate the the association of NQO1 C609T with the risk of hepatocellular carcinoma (HCC) development among Turkish population. NQO1 C609T polymorphism was investigated in 167 confirmed subjects with HCC and 167 cancer-free control subjects matched on age, gender, smoking and alcohol consumption by using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. There is no association between the allel or genotype of NQO1 C609T polymorphism and HCC development risk in the Turkish subjects examined (p>0.05). Our result demonstrate for the first time that the NQO1 C609T polymorphism is not a genetic susceptibility factor for HCC in the Turkish population. Independent studies are need to validate our findings in a larger series, as well as in patients of different ethnic origins.
Asian Pacific journal of cancer prevention: APJCP 01/2010; 11(4):1051-8. · 0.66 Impact Factor
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ABSTRACT: Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine that may act as an endogenous tumor promoter. A genetic polymorphism of TNF-alpha gene at position -308 promoter region is involved in the regulation of expression level and has been found to be associated with susceptibility to various types of cancer.
To determine the association of the TNF-alpha gene G-308A polymorphism on the risk of hepatocellular carcinoma (HCC) in a Turkish population, a hospital-based case-control study was designed consisting of 110 diagnosis subjects with hepatocellular carcinoma and 110 cancer-free control subjects matched on age, gender, smoking and alcohol status. The genotype frequency of this polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.
The distribution G-308A genotype was significantly associated with the risk of HCC (p<0.001, odds ratio [OR]=4.75, 95% confidence interval [CI]=2.25-9.82 for -308 AA/GA genotypes versus GG genotype).
We suggested that the presence of the high producer allele -308A in the TNF-alpha gene appears to be associated with an increased risk for the development of HCC in Turkish population.
Cancer epidemiology. 08/2009; 33(3-4):261-4.
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ABSTRACT: The aim of this study was to investigate genotoxic effects of lamivudine (an analogue of cytidine) using in vitro sister chromatid exchange (SCE), chromosome aberration (CA), and micronucleus (MN) tests in human peripheral lymphocytes. The cells were treated with 75, 100, 125, and 150 microg/ml concentrations of lamivudine (roughly 30-60 times higher than plasma levels achieved in patients receiving this drug) for two (24- and 48-hr) treatment periods. Lamivudine induced SCEs at the highest concentration (150 microg/ml) in the 24-hr treatment, and at 125 and 150 microg/ml in the 48-hr treatment, when compared to the solvent control. During both treatment periods, structural chromosome aberrations were significantly increased at 100, 125, and 150 microg/ml lamivudine concentrations. However, the increases of SCEs (22%) and CAs (50%) were weak. In addition, lamivudine reduced both the proliferation index (PI) and the mitotic index (MI) significantly at all concentrations for the two treatment periods. The MI was reduced by lamivudine in a dose-dependent manner during both the 24- and 48-hr treatment periods. In contrast, the PI was reduced by lamivudine only during the 48-hr treatment period. A weak but significant increase in MN formation was observed following lamivudine treatment at 100, 125, and 150 microg/ml for 48 hr, but no significant increase in micronuclei were observed following 24-hr treatment. In conclusion, lamivudine has a weak genotoxic effect at elevated doses on human peripheral lymphocytes.
Environmental and Molecular Mutagenesis 06/2008; 49(4):328-33. · 3.71 Impact Factor
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ABSTRACT: Background: Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine that may act as an endogenous tumor promoter. A genetic polymorphism of TNF-α gene at position −308 promoter region is involved in the regulation of expression level and has been found to be associated with susceptibility to various types of cancer. Methods: To determine the association of the TNF-α gene G-308A polymorphism on the risk of hepatocellular carcinoma (HCC) in a Turkish population, a hospital-based case-control study was designed consisting of 110 diagnosis subjects with hepatocellular carcinoma and 110 cancer-free control subjects matched on age, gender, smoking and alcohol status. The genotype frequency of this polymorphism was determined by using a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay. Results: The distribution G-308A genotype was significantly associated with the risk of HCC (p < 0.001, odds ratio [OR] = 4.75, 95% confidence interval [CI] = 2.25–9.82 for −308 AA/GA genotypes versus GG genotype). Conclusion: We suggested that the presence of the high producer allele −308A in the TNF-α gene appears to be associated with an increased risk for the development of HCC in Turkish population.
Cancer Epidemiology.
