الفهرس 
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Abstract
HCC is the 6th most common cancer in the world and the 4th most common cause of cancer death. In Egypt, HCC is the most common cancer in men and the second most common in women. It has been documented that liver cirrhosis is the most important risk factor for HCC development. Other major risk factors for HCC include viral infections as HCV and HBV, alcohol and non- alcoholic fatty liver, smoking, aflatoxin, diabetes and genetic risk factors.
In Egypt, although the relationship between HCV and the development of HCC is well established, the pathogenetic mechanism of hepatocarcinogensis including host and viral genetic factors is still unknown. Among these factors, single nucleotide polymorphism of MCP-1-2518 A/G and CCR2 (V64Ile) genes have been suggested.
The aims of this work were to: 1) study the different genotypes of MCP-1-2518 A/G and CCR2 (V64Ile) genes in patients with liver cirrhosis and hepatocellular carcinoma in comparison to normal controls. 2) study serum level of MCP-1 protein in the studied groups and its relation to different MCP-1-2518 A/G genotypes. 3) investigate the relationship between MCP-1-2518 A/G and CCR2 (V64Ile) genotypes and liver cirrhosis severity assessed by Child classification. 4) study the relationship of different MCP-1-2518 A/G and CCR2 (V64Ile) genotypes to the risk of HCC in cirrhotic patients.
This case control study was conducted in Medical Microbiology and Immunology, Tropical Medicine and Gastroenterology departments and Central Research Laboratory, Faculty of Medicine, Sohag University during the period from September 2018 to May 2019. The study included 65 patients (35 HCV-related HCC and 30 patients with HCV-related liver cirrhosis. In addition, 28 age and sex- matched healthy subjects were included as a control group. Informed written consent was obtained from all participants. The study protocol was approved by the Ethics Committee of Sohag Faculty of Medicine.
All participants were subjected to complete medical history, clinical examination, laboratory investigations including complete blood count, liver functions tests and AFP (for patients with hepatic focal lesion only) and abdominal ultrasonography. Triphasic CT scan of the abdomen was done if a hepatic focal lesion was detected by ultrasonography to establish the diagnosis of HCC. Genotyping of MCP-1-2518 A/G and CCR2 (V64Ile) were done by Real time PCR. Serum level of MCP-1 was measured by ELISA.
For MCP-1-2518 A ̸ G gene, HCC patients had a statistically significant higher frequency of AG and GG genotypes and lower frequency of AA genotypes compared to patients with liver cirrhosis and control group (P=0.045 & 0.0001 respectively). As regard CCR2 (V64Ile), HCC patients had statistically significant higher frequency of GA, AA genotypes (P= 0.001 & 0.0001 respectively) and lower frequency of GG genotypes compared to liver cirrhosis and controls (P= 0.001& 0.0001 respectively).
Mean serum level of MCP-1 was significantly higher in LC and HCC groups compared to the controls (P=0.0001 for each). Similarly, it was significantly higher in HCC than LC group (P=0.0001). No statistically significant differences were found among different genotypes in HCC patients as regard serum level of MCP-1. The carriage of CCR2 (V64Ile) AA, GA genotypes in liver cirrhosis group had statistically significant association with more severe liver disease compared to CCR2 (V64Ile) GG genotype.
Univariate and multivariate analysis of our data revealed that smoking, high serum MCP-1, GA and AA genotypes of CCR2 (V64Ile) and Child class C were independent predictors of HCC in HCV-related liver cirrhosis.
In conclusion, our study demonstrates a significant association between CCR2- (V64Ile) polymorphism (AA, GA genotypes), high serum level of MCP-1 protein and HCC development. The CCR2 AA, GA genotype may be used as molecular markers to predict the risk of HCC in patients with HCV-related liver cirrhosis.
Recommendations
• Genetic factors particularly gene polymorphisms should be taken in consideration on addressing risk factors for development of HCC.
• The characterization of CCR2 (V64Ile) polymorphism (AA, GA genotypes) in patients with HCV-related liver cirrhosis could help to identify those who are at high risk of developing HCC.
• The influence of ethnicity on the distribution of MCP-1-2518 A/G and CCR2 (V64Ile) gene polymorphisms and its association with the risk of HCC should be demonstrated in further studies.
• Estimation of serum level of MCP-1 in patients with HCV- related liver cirrhosis and may help to identify those who are at high risk of developing HCC.
• Further large controlled clinical trials are required to validate our observations and to evaluate the impact of MCP-1-2518 A/G and CCR2 (V64Ile) gene polymorphisms and serum level of MCP1at different sites on the risk of HCC development in patients with HCV-related liver cirrhosis.
• Further studies should be done on patients with liver cirrhosis due to other aetiologies (e.g. HBV) to evaluate the impact of MCP-1 and CCR2 gene polymorphisms and serum level of MCP-1 on the risk of HCC development.