Aynur Bekar

A functional polymorphism in pre-microRNA-196a-2 contributes to the susceptibility of hepatocellular carcinoma in a Turkish population: a case–control study

Summary.  MicroRNAs (miRNAs) are an abundant class of small nonprotein‐coding RNAs with posttranscriptional regulatory functions as tumour suppressors and oncogenes. Aberrant expression and structural alteration of miRNAs are thought to participate in tumourigenesis 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 development of human cancers. Recent studies have indicated that the miR‐196a‐2 rs11614913 (C→T) polymorphism could alter mature miR‐196a‐2 expression and target mRNA binding. To determine the association of the miR‐196a‐2 rs11614913 polymorphism with the risk of hepatocellular carcinoma (HCC) development in a Turkish population, a hospital‐based case–control study was designed consisting of 185 subjects with HCC and 185 cancer‐free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the miR‐196a‐2 rs11614913 polymorphism was determined by using a polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay. Our data shows that the CC genotype of the miR‐196a‐2 rs11614913 polymorphism is associated with increased risk of HCC development in this Turkish population (OR = 2.41, 95% CI: 1.30–4.50, P = 0.005). Furthermore, according to stratified analysis, a significant association was observed between the homozygote CC genotype and HCC risk in the subgroups of male gender (OR = 3.12, 95% CI: 1.53–6.34, P = 0.002) and patients with hepatitis B virus (HBV)‐related HCC (OR = 2.88, 95% CI: 1.33–6.22, P = 0.007). Because our results suggest for the first time that the miR‐196a‐2 rs11614913 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.

G-308A TNF-α polymorphism is associated with an increased risk of hepatocellular carcinoma in the Turkish population: case-control study.

BACKGROUND 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. METHODS 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. 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-alpha gene appears to be associated with an increased risk for the development of HCC in Turkish population.

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.

MDM2 promoter polymorphism is associated with increased susceptibility to hepatocellular carcinoma in Turkish population.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION Our findings suggest that the MDM2 promoter SNP309 G allele is associated with presence of HCC in Turkish population.

The association between the survivin -31G/C promoter polymorphism and hepatocellular carcinoma risk in a Turkish population.

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSION 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.

Relationship between functional polymorphism in the Aurora A gene and susceptibility of hepatocellular carcinoma

Summary.  Aurora A is considered a potential cancer susceptibility gene owing to overexpression or amplification of Aurora A gene that causes centrosome dysfunction, chromosome instability, tumourigenic transformation and checkpoint abnormalities. Functional coding region polymorphism F31I in the Aurora A gene has recently been shown to be associated with several human cancers, but its association with hepatocellular carcinoma (HCC) has yet to be investigated. Genetic polymorphism of Aurora A was investigated in 128 confirmed subjects with HCC and 128 cancer‐free control subjects matched on age, gender, smoking and alcohol consumption by using a polymerase chain reaction–restriction fragment length polymorphism assay. Allele and genotype associations of Aurora A F31I polymorphism with HCC susceptibility were observed in comparisons between the patient and control samples (respectively; P = 0.005, P = 0.012). The proportion of the genotypes containing I31 allele in patients with HCC (39.8%) was significantly higher than that in patients without HCC (22.7%) (P = 0.003). The distribution F31I genotype was significantly associated with increased risk of HCC (P = 0.003, odds ratio = 2.26, 95% confidence interval = 1.31–3.90 for FI + II genotypes vs FF genotype). Our results suggest for the first time that the Aurora A F31I polymorphism may be a genetic susceptibility factor for HCC.

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.

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.

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.