الفهرس 
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Abstract
The rate of hepatitis C virus (HCV) infection in Egypt is among the highest in the world, and several investigations in Egypt had shown the increasing importance of HCV infection in the etiology of liver cancer. In Egypt, liver cancer constitutes 11.75% of all digestive organs malignancies and 1.68% of the total malignancies. from all liver tumors diagnosed, hepatocellular carcinoma (HCC) represents about 70.48%.
Although the vast majority of DNA polymorphisms are situated in non-coding regions, some can modify gene-product expression and function, which may affect biological pathways. If the genes are involved in liver carcinogenesis, these modifications may partly explain the genetic heritability thought to influence individual susceptibility to HCC.
The association of methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) gene polymorphisms with HCC occurrence remains controversial. Therefore, the main goal of the present study was to assess the association of MTHFR C677T, MTHFR A1298C, and TS 3’-UTR 1494del/ins 6bp polymorphism with the susceptibility to HCC in Egyptian HCV-cirrhotic patients.
This is a case-control study conducted in the period between August 2016 and February 2019 in which 194 HCV-infected patients subdivided into 104 HCV-cirrhotic and 90 HCC patients were sequentially recruited from inpatients and the outpatient clinic of the Tropical Medicine and Hepatology Department, Faculty of Medicine, Mansoura University. Additionally, 100 age- and sex-matched participants with no underlying liver diseases recruited from healthy blood donors at Mansoura University Hospitals were included in the study.
Written informed consent was obtained from each participant before the start of the study. This work was carried out per The Declaration of Helsinki and approved by the local ethical committee of Faculty of Medicine, Mansoura University, Dakahlia, Egypt.
All subjects were subjected to
• Full history and clinical examinations.
• Determination of liver function tests including the activities of alanine transaminase (ALT) and aspartate transaminase (AST) as well as total bilirubin and albumin levels.
• Determination of Alpha-fetoprotein (AFP) levels.
• Detection of MTHFR C677T, MTHFR A1298C, and TS 3’-UTR 1494del/ins 6bp polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.
The results of the study can be summarized as follows
• Compared to the control group, LC and HCC patients had significantly higher ALT and AST activities, in addition to total bilirubin and AFP levels; in contrast, a significant decrease in albumin concentration was noted.
• In comparison with LC patients, HCC patients had significantly higher ALT activity, in addition to albumin and AFP levels.
• The genotypic distribution of the three polymorphisms was consistent with Hardy-Weinberg equilibrium (HWE) in all groups.
• For MTHFR C677T SNP, there was no significant difference in the genotype distribution and allele frequency when LC patients were compared to the control group. On the other hand, HCC patients showed a significantly higher frequency of TT genotype with the decrease of CC and CT genotypes compared to controls. In the same context and compared to LC patients, HCC patients showed a significantly higher frequency of TT genotype with the decrease of CC genotype. Accordingly, HCC patients had higher MTHFR 677T allele frequency than normal subjects and LC patients.
• The MTHFR C677T SNP was associated with an increased risk of HCC in controls under the homozygous codominant, recessive, and allelic models after adjusting for sex and age.
• The same results were observed in LC patients with an increased risk to develop HCC under all tested models after adjusting for sex and age.
• Regarding MTHFR A1298C SNP, LC and HCC patients showed a significantly higher frequency of CC and AC genotype with the decrease of AA genotype compared to the control group. Consequently, LC and HCC patients had higher MTHFR 1298C allele frequency than normal subjects. On contrary, no statistically significant differences were detected between LC and HCC patients in either the genotypic or allelic frequencies.
• The MTHFR A1298C SNP in controls was associated with an increased risk of HCC under all tested models after adjusting for sex and age.
• Except for the homozygous codominant model, no significant association with HCC risk was found under any of the tested genetic models in LC patients after adjusting for sex and age.
• When considering TS polymorphism, the results showed that there was no significant difference in the genotype distribution and allele frequency between the studied groups.
• TS polymorphism was associated significantly with HCC risk only under the allelic model in controls. Moreover, it was associated significantly with HCC risk only under the homozygous codominant model in LC patients.
• The results of pairwise linkage disequilibrium estimates obtained for the three gene polymorphisms of MTHFR C677T and A1298C in addition to TS 1494del/ins 6 bp showed that there was almost no disequilibrium between the three polymorphisms.
• Haplotypes of the MTHFR polymorphisms were constructed and analyzed for their association with HCC. The C/C and T/C haplotype combination of MTHFR C677T and MTHFR A1298C conferred increased the risk for healthy subjects to develop HCC. On the contrary, the T/C haplotype only contributed to increased risk of LC patients to develop HCC.
In summary, the present study identified the association of gene variants of MTHFR and TS in addition to the MTHFR haplotypes with increased susceptibility to HCV-related HCC in an Egyptian population. These results seem to be promising for oncogenomics to be used in programs of early cancer diagnosis as well as cancer prevention.