Süleyman Bayram

No association of pre-microRNA-146a rs2910164 polymorphism and risk of hepatocellular carcinoma development in Turkish population: A case-control study

AIM 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. METHODS 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. RESULTS 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). CONCLUSION 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.

RASSF1A Ala133Ser polymorphism is associated with increased susceptibility to hepatocellular carcinoma in a Turkish population

AIM The tumor suppressor gene Ras association domain family 1 isoform A (RASSF1A) regulates cell cycle regulation, apoptosis and microtubule stability and is inactivated by promoter hypermethylation at a high frequency in hepatocellular carcinoma (HCC). A guanine (G)/thymine (T) common single nucleotide polymorphism (SNP) at first position of codon 133 in RASSF1A gene determines an alanine (Ala) to serine (Ser) (Ala133Ser) amino acidic substitution which may alter cancer risk by influencing the function of RASSF1A protein. METHODS To determine the association of the RASSF1A Ala133Ser polymorphism with the risk of HCC development in a Turkish population, a hospital-based case-control study was designed consisting of 236 subjects with HCC and 236 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the RASSF1A Ala133Ser polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS Allele and genotype associations of RASSF1A Ala133Ser polymorphism with HCC susceptibility were observed in comparisons between the patient and control samples (P<0.001). Risk of HCC development in this Turkish population was significantly increased in carriers of the Ser133 variant allele of Ala133Ser polymorphism (Ala/Ser and Ser/Ser genotypes) when compared with homozygote Ala/Ala genotype (OR=5.47, 95% CI=3.63-8.25, P=0.001). CONCLUSION Because our results suggest for the first time that the Ser133 allele of RASSF1A Ala133Ser 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.

CHEK2 1100delC, IVS2+1G>A and I157T mutations are not present in colorectal cancer cases from Turkish population

BACKGROUND 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. METHODS 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. RESULTS We did not find the CHEK2 1100delC, IVS2+1G>A and I157T mutations in any of the Turkish subjects. CONCLUSION 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.

Effect of PON1 gene polymorphisms in Turkish patients with hepatocellular carcinoma

Background: Reactive oxygen species (ROS) can oxidize biological molecules that mediate carcinogenesis by causing metabolic malfunction and damage to DNA. Human serum paraoxonases (PON1, PON2 and PON3) play a role in antioxidant defense and protect the cell against ROS. PON1 polymorphisms Q192R and L55M have been shown to be associated with several human cancers, but their association with hepatocellular carcinoma (HCC) has yet to be investigated. Methods: We performed genotyping analysis using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a hospital-based case–control study of 217 confirmed HCC patients and 217 age-, gender-, smoking- and alcohol consumption-matched cancer-free controls in Turkish population. Results: Q192R and L55M polymorphisms were in significant linkage disequilibrium (LD) (D′ = 0.77). However, allele, genotype and haplotype analysis showed no significant differences between the risks of HCC and PON1 polymorphisms. Moreover, no significant differences were found between clinical findings, clinicopathological features and sex in comparison with the PON1 genotypes in HCC group. Conclusion: Our results suggest for the first time that neither the Q192R polymorphism nor the L55M polymorphism has relationship with the risk of developing HCC. Further independent studies are required to clarify the possible role of PON1 gene Q192R and L55M polymorphisms on the risk of developing HCC in a larger series and also in patients of different ethnic origins.

Prevalence of Beta-Thalassemia Trait and Abnormal Hemoglobins in the Province of Adıyaman, Turkey

Background/Aims: Thalassemia is one of the most common hereditary disorders in Turkey. The aim of this study was to determine the prevalence of the beta-thalassemia trait and abnormal hemoglobins in the province of Adıyaman in Turkey. Methods: The study included 3571 high school students of both sexes; aged 12–22 (mean 16.59 ± 1.34). After they received information about thalassemia, they were screened for beta-thalassemia and abnormal hemoglobin using complete blood count (CBC) and quantification of hemoglobin. Hemoglobin was fractionated using HPLC. Results: The beta-thalassemia trait was found in 38 students (1.06%), and abnormal hemoglobin in seven students (0.20%). Of the latter, four carried HbD Los Angeles, two HbS, and one HbE-Saskatoon. Conclusion: The prevalence of the beta-thalassemia trait and abnormal hemoglobin in the province of Adıyaman is low, compared to the rest of Turkey. Our results seem to reflect the heterogeneity of beta-thalassemia in the province of Adıyaman and may be of value for genetic counseling and premarital screening.

Lack of an association of programmed cell death-1 PD1.3 polymorphism with risk of hepatocellular carcinoma susceptibility in Turkish population: a case-control study.

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.

Polymorphisms in human telomerase reverse transcriptase (hTERT) gene and susceptibility to gastric cancer in a Turkish population: Hospital-based case–control study

Erosion of telomeres, tandem nucleotide repeats (TTAGGG)n that cap the end of eukaryotic chromosomes, has been related with carcinogenesis. The human telomerase reverse transcriptase (hTERT) gene is encoded the rate-limiting catalytic subunit of the telomerase complexes, which is essential for the protection of telomeric DNA length and chromosomal stability. The purpose of this study was to examine the effect of four functional single nucleotide polymorphisms (SNPs) of hTERT (rs2736109 G>A, rs2735940 T>C, rs2853669 A>G and rs2736100 T>G) on susceptibility to gastric cancer (GC) in Turkish population. The genotype frequency of hTERT rs2736109 G>A, rs2735940 T>C, rs2853669 A>G and rs2736100 T>G polymorphisms were determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan methods in 104 subjects with GC and 209 healthy control subjects. We found that hTERT rs2736109 G>A (AA+AG vs. GG OR=1.68 95% CI=1.01-2.81, P=0.04), rs2735940 T>C (CC vs. CT+TT: OR=2.53 95% CI=1.01-6.13, P=0.03), and rs2736100 T>G (TT vs. TG+GG: OR=2.27 95% CI=1.23-4.17, P=0.006) polymorphisms were associated with risk of GC. In the haplotype analysis, hTERT Grs2736109/Trs2735940/Ars2853669/Grs2736100 haplotype was also related with an increased risk of GC (OR=1.75; 95% CI: 1.05-2.93, P=0.03). Because this is the first study regarding the hTERT rs2736109 G>A, rs2735940 T>C, rs2853669 A>G and rs2736100 T>G polymorphisms and the risk of GC susceptibility in the literature, further independent studies are needed to verify our results in a larger sample sizes, as well as in patients of different populations.

Relationship between programmed cell death-1 polymorphisms and clearance of hepatitis B virus

Programmed cell death‐1 (PD‐1) plays a critical role in regulating T‐cell function during hepatitis B virus (HBV) infection. This study investigated the relationship between the polymorphisms of PD‐1 gene and the susceptibility to HBV infection. Single nucleotide polymorphisms (SNPs) in PD‐1 gene at positions +7146 G>A (guanine to adenine substitution) and +7209 C>T (cytosine to thymine substitution) were analysed using a polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP) method in 220 subjects with chronic hepatitis B infection and 165 spontaneous clearance of HBV subjects. However, no statistically significant differences were found in the genotype distributions of the PD‐1 +7146 G>A and PD‐1 +7209 C>T polymorphisms among chronic hepatitis B and spontaneous clearance subjects. According to stratified analyses, borderline significance was observed between PD‐1 +7146 GA genotype and risk of HBV chronicity in the subgroup of male gender (OR = 1.88, 95% 0.95–3.71; P = 0.07). Our findings demonstrate for the first time that the PD‐1 +7146 G>A and PD‐1 +7209 C>T polymorphisms have not been any major role in genetic susceptibility to chronicity of HBV infection, 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.

The exonuclease 1 Glu589Lys gene polymorphism and cancer susceptibility: evidence based on a meta-analysis.

BACKGROUND Published studies on the association between the exonuclease 1 (EXO1) Glu589Lys polymorphism and cancer susceptibility have yielded conflicting results. Thus, a meta-analysis of published studies was performed to assess the possible association. MATERIALS AND METHODS All eligible case-control studies published up to January 2013 on the association between the EXO1 Glu589Lys polymorphism and cancer susceptibility were identified by searching PubMed, Web of Science, Science Direct and hand search. Either fixed-effect or random-effect models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs) using the Comprehensive Meta-Analysis software version 2.2. RESULTS A total of 4,391 cancer cases and 4,339 controls from 10 studies were included. Overall, no significant association between the EXO1 Glu589Lys polymorphism and cancer susceptibility was observed in either genetic model. However; in subgroup analyses by cancer type, a significant association between EXO1 Glu589Lys and lung cancer risk was found (Lys vs Glu: OR=1.23, 95%CI=1.07- 1.41, p heterogeneity=0.05). Further, subgroup analysis by ethnicity indicated that there was a statistically increased cancer risk in Asians (Lys vs Glu: OR=1.42, 95%CI=1.30-1.55, p heterogeneity=0.07; Lys/Lys vs Glu/Glu: OR=1.93, 95%CI=1.20-3.12, p heterogeneity=0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR=1.52, 95%CI=1.37-1.68, p heterogeneity=0.42; Lys/Lys vs Glu/Lys+Glu/Glu: OR=1.68, 95%CI=1.07-2.65, p heterogeneity=0.02). However, significant association was absent in Caucasians. CONCLUSIONS This meta-analysis suggests, for the first time, that the EXO1 Glu589Lys polymorphism is not associated with overall cancer susceptibility, although marginal associations were found for lung cancer and Asian subgroups. Additional well-designed studies with larger sample size focusing on different ethnicities and cancer types are needed to confirm these findings.

Association between RASSF1A Ala133Ser polymorphism and cancer susceptibility: a meta-analysis involving 8,892 subjects.

BACKGROUND Published studies on the association between the Ras Association Domain Family 1 isoform A (RASSF1A) Ala133Ser polymorphism and cancer susceptibility have yielded conflicting results. Thus, a meta- analysis was here performed to assess the possible association. MATERIALS AND METHODS All eligible case-control studies published up to November 2013 on the association between RASSF1A Ala133Ser polymorphism and cancer susceptibility were identified by searching PubMed, Web of Science, Science Direct and hand search. Bothfixed- effect and random-effect models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs) by using the Comprehensive Meta-Analysis software version 2.2. RESULTS A total of 10 studies including 4,572 cancer cases and 4,320 controls were included in the meta-analysis. Overall, significantly increased cancer risk was associated with the variant Ser133 when all studies were pooled (Ser vs Ala: OR=1.51, 95% CI=1.08- 2.12, Pheterogeneity≤0.001; Ser/Ser+Ala/Ser vs Ala/Ala: OR=1.55, 95% CI=1.08-2.22, Pheterogeneity ≤ 0.001). Moreover, in subgroup analyses by cancer types, a significant association between RASSF1A Ala133Ser polymorphism and lung cancer risk was found (Ser vs Ala: OR=2.27, 95% CI=1.29-4.02, Pheterogeneity=0.61; Ser/Ser+Ala/ Ser vs Ala/Ala: OR=2.42, 95% CI=1.33-4.42, Pheterogeneity=0.75). In addition, in subgroup analyses by ethnicity, it was found that the RASSF1A Ala133Ser polymorphism was associated with overall cancer risk in Asians (Ser vs Ala: OR=1.37, 95% CI=1.06-1.77, Pheterogeneity=0.06) and Caucasians (Ser/Ser+Ala/Ser vs Ala/Ala: OR=2.21, 95% CI=1.01-4.82, Pheterogeneity≤0.001). CONCLUSIONS This meta-analysis suggests, for the first time, that RASSF1A Ala133Ser polymorphism may contribute to cancer susceptibility, especially for lung cancer. Besides, additional well-designed studies with larger sample size focusing on different ethnicities and cancer types are needed to confirm these findings.