الفهرس 
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Abstract
Hepatocellular carcinoma is the sixth most common cancer worldwide, with liver cancer accounting for 9.1 % of global cancer mortality. Egypt has a high incidence of HCC reaching about 21% in cirrhotic Egyptian patients. HCV and HBV infections, diabetes mellitus are the main determinants of HCC development in Egypt.
Tp53 (tumor protein 53), is a tumor suppressor protein that is encoded by the Tp53 gene. It plays a key role in stress responses like DNA damage, hypoxia, metabolic stress and oncogene activation and maintains genomic integrity. TP53 exerts its protective roles as a transcription factor, by binding to specific response elements in DNA; Tp53 modulates the transcription of genes that govern the major defenses against tumor growth, which include cell cycle arrest, apoptosis, inhibition of angiogenesis and cellular senescence.
Several studies reported an association between the TP53 Arg72Pro polymorphism and an increased risk for HCC. However, to the best of our knowledge the role of Tp53 polymorphism as risk factor of HCC in chronic hepatitis has not been studies in Upper Egypt. Therefore, we conducted our study aiming to;
1. To study serum level of Tp53 protein in chronic hepatitis C, liver cirrhosis and HCC patients in comparison to healthy controls.
2. To assess the relationship between Tp53 serum level and the degree of liver dysfunction in liver cirrhosis and hepatocellular carcinoma.
3. To study the different Tp53 genotypes in different forms of hepatitis C induced chronic liver diseases in comparison to healthy control.
4. To assess the relationship between serum level of Tp53 protein and the different genotypes.
5. To investigate whether Tp53 polymorphism is a risk factor for development of hepatocellular carcinoma in chronic hepatitis C patients.
One hundred subjects were recruited for the study of these 20 patients had chronic hepatitis C , 40 patients had HCV-related liver cirrhosis and 20 patients had HCV-related hepatocellular carcinoma on top of liver cirrhosis. In addition 20 age and sex matched healthy subjects were included as a control group. Before inclusion, the study protocol was approved by Sohag Faculty of Medicine Ethical Committee and all participants signed an informed consent.
Patients excluded from the study if they had Co-infection with Hepatitis B; DM; Autoimmune hepatitis and patients with other causes of liver cirrhosis as Wilson’s diseases, hemochromatosis and alcoholic cirrhosis.
All participants were subjected to complete medical history taking, clinical examination and laboratory investigations including complete blood count, liver function tests, hepatitis markers and serum creatinine.
Abdominal ultrasound was done for all participants. If we found any hepatic focal lesion triphasic abdominal CT or MRI was done to confirm the diagnosis of HCC. AFP was measured if a hepatic focal lesion was detected by ultrasonography .
Tp53 serum level was measured by ELISA and Tp53 gene codon 72 genotyping was performed by PCR-RFLP technique.
This study showed a significant difference in the distribution of TP53 genotypes among study groups. Patients with HCC had a statistically significant higher frequency of CC (pro/pro) genotype in comparison with CHC group and control groups .
Also, the risk of developing HCC was 2.658 times higher in patients with the CC genotype than in patients with the GG genotype and GC genotype and this difference was statistically significant (95% CI: (0.435-16.24)).
In this result showed a significant decrease in platelet count in HCC group in comparison to CHC and control groups ( p = 0.0001,0.0001 respectively). Patients with HCC had significantly higher Child score than LC group (p= 0.0001). A significant negative correlation was found between Tp53 serum level and MELD Score in both LC and HCC groups.
Mean serum Tp53 was significantly higher in HCC group than LC, CHC and control groups (p= 0.00l , 0.0001, 0.0001 respectively). In LC group, mean serum Tp53 was significantly in Child A patients than Child B and C.
Analysis of Tp53 codon 72 by PCR-RFLP revealed that pro/pro (CC genotype) was the most frequent type in HCC group (40%) and it was significantly more frequent in HCC than CHC and control groups ( 40% ,10% and 10%, p= 0.009 and 0.03 respectively).
Studying the relationship between Tp53 serum level and different genotypes in the studied group revealed no significant association except in HCC group where Tp53 was significantly higher in GG genotype.
On the studying the independent predictors for development of HCC in patients with HCV-related liver cirrhosis, univariate binary logistic regression analysis revealed that age, platelet count, carriage of CC genotype of Tp53 gene and Tp53 serum level were the factors significantly associated with HCC development. Multivariate binary logistic regression analysis confirmed that carriage of CC genotype (odds ratio (OR): 2.658, 95% confidence interval (CI 95%): 0.435-16.24, P <0.01) , platelet count (OR: 1.02, CI 95%: 1.002-1.02, P = 0.01), and Tp53 serum level (odds ratio (OR): 0.801,95% confidence interval (CI 95%): 0.713-0.900, P <0.0001) were the factors that predicted development of HCC in HCV-related liver cirrhosis.
In conclusion, plasma Tp53 protein level could be considered as an additional tumor marker to AFP to increase the diagnostic potential of AFP in HCC patients. Also, this study suggests that the Tp53 codon 72 polymorphism CC genotype may be associated with liver cancer in HCV related LC. Finally, Tp53 gene polymorphism could be used as an indicator of the genetic susceptibility that might carry the risk of future development of HCC in Egyptian cirrhotic patient.
Conclusion
Serum Tp53 and pro/pro (CC genotype) are significantly associated with hepatocellular carcinoma. Older age , low platelet count ,Tp53 serum level and CC genotype are independent predictors of HCC in univariate analysis. Multivariate analysis confirmed that low platelet count ,Tp53 serum level and CC genotype are the factors that significantly predict HCC development in HCV-related liver cirrhosis.
Recommendations
The applicable use of non-invasive biomarkers as TP53 codon 72 gene polymorphism and TP53 serum level are advantageous compared with other invasive methods .
• Further independent studies are required to validate our findings in a large series, as well as in patients of different ethnic origins.
• Further studies are needed to show the role of Tp53 and its gene polymorphism in HCC development in Hepatitis B cirrhotic patients and alcoholic cirrhosis.
• The knowledge of mechanism involved in HCC carcinogenesis may help to identify targets for the development of chemoprevention or therapeutic strategies.
Limitations of study
Our findings are based on a single center study with a small sample size, a fact that makes it difficult to generalize our results to all patients with HCV-related liver cirrhosis Multicenter studies using the same protocol and examining a larger number of patients with different ethnic groups are needed.