الفهرس 
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Abstract
Hepatocellular carcinoma (HCC) is a primary cancer of chronically injured liver by infection, metabolic disease or various drugs. As generally observed in other carcinomas, HCC is attributed to accumulated genetic alterations. HCC is one of the most common malignant tumors worldwide that represent the fifth most malignant tumor worldwide and the third most common cause of cancer mortality.
The increased prevalence of HCC is related to the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and the growing incidence of fatty liver diseases due to metabolic disorders and alcohol abuse. Currently, the incidence of HCC seems to be increasing tremendously in Egypt as pointed out by many studies. In the recent past, HCC has become the second most prevalent cancer among men in Egypt. .
HCC can be managed according to the stage of the tumor with surgical resection or transplantation in selected cases, whereas advanced tumor responds poorly to currently available medical therapies. Potentially curative treatments include surgical resection and liver transplantation, with reported 5-year survival of 50–70%. Surgical resection is a potentially curative therapy for HCC; however, only 10%-30% of patients with HCC are eligible for curative hepatectomy.
The understanding of the molecular pathways leading to the development of (HCC) may provide important data to develop new therapies, similar to other tumor types, an imbalance between
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unrestrained cell proliferation and impaired apoptosis appear to be a major unfavorable feature of (HCC).
Recent studies have documented the over expression of anti apoptotic factors such as inhibitors of apoptosis proteins (IAPs) in a variety of solid tumors and cancer cell lines.
Survivin, a member of the inhibitor of apoptosis (IAP) family of proteins, regulates two essential processes. It inhibits apoptosis and promotes cell proliferation. Although expressed at high levels during fetal development, survivin is rarely expressed in normal healthy adult tissues. It is however, up regulated in the majority of cancers including stomach, colorectal, breast and pancreatic carcinoma.
Because of this up regulation in malignancy and its functional involvement in apoptosis as well as proliferation, survivin is currently attracting considerable interest both as a potential cancer biomarker and as a new target for cancer treatment.
The aim of this study is to assess the differential expression of survivin gene in tumorous versus non tumorous liver tissue of HCC patients and determine the possible influence of survivin gene polymorphism -31G/C (rs9904341) and +9809 T/C (rs1042489) on its expression and its involvement in the risk of HCC in Egyptian patients.
This study was conducted on 30 cases with hepatocellular carcinoma, presented to Hepatobiliary surgery Department, National Liver Institute, Menoufia University in the period from October 2011 to October 2012. Patients with HCC underwent surgical resection and tissue samples were taken from tumorous and corresponding non
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tumorous liver tissue. In addition to 30 unrelated apparently healthy subjects with matching age and gender served as control group.
All patients and control groups were subjected to the following:
1. Full history taking.
2. Complete clinical examination.
3. Abdominal ultrasonography and CT.
4. Laboratory investigations including: complete blood picture, liver function tests, viral markers (HBsAg, HCV-Ab), estimation of serum AFP and molecular testing for
- Genotyping of survivin gene polymorphism -31G/C (rs9904341).
- Genotyping of survivin gene polymorphism +9809T/C (rs1042489).
- Survivin gene expression (mRNA).
- The results from the current study showed the following:
The groups were homogenous regarding age and gender. The mean age of HCC patients in this study was 55.97±11.11 years.
There was statistical significant increase of mean serum level of ALT, AST, ALP, GGT, INR, AFP and number of patients positive for HCV Ab in HCC patients compared to controls. There was statistical significant decrease in platelets and PC% in HCC patients compared to controls.
There was no statistical significant difference between group Ia, Ib and II regarding genotypes and alleles frequency of survivin -31G/C (rs9904341) and +9809 T/C (rs1042489).
There was no association between different genotypes and alleles of -31G/C (rs9904341) and +9809 T/C (rs1042489) and risk of incidence of HCC.
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There was no statistical significant difference between genotypes and alleles of survivin-31G/C (rs9904341) and survivin +9809 T/C (rs1042489) in tumorous tissue regarding survivin expression, cirrhosis, stage, size, number, type of tumor, vascular invasion, AFP and liver function tests.
Three mutations were detected in tumorous versus non tumorous liver tissue specimens at survivin -31G/C (one case) and +9809 T/C (two cases). The change was toward C allele in tumorous specimens.
The current study found that survivin mRNA was found in all tissue specimens (tumorous and non tumorous) and survivin mRNA was over expressed in tumorous tissues by (13) fold.
The present study showed a high statistical significant increase of survivin expression in tumorous tissue compared to non tumorous tissue in HCC patients (p < 0.001).
There was statistical significant increase of survivin expression in tumorous tissues in HCC patients with advanced stage of tumor, larger size of tumor, vascular invasion and without cirrhosis (p < 0.05). Significant positive correlation was detected between AFP and survivin expression in tumorous tissues.
No difference in survivin expression regarding type and number of focal lesions of the tumor.
HCC patients who have recurrence within one year showed high significant increase in survivin expression in tumorous tissues compared to those had no recurrence (p < 0.001).
The current study showed that there was significant difference between cases of high survivin expression and cases of lower survivin expression regarding overall survival rate (70%) and
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disease free survival rate (53.3%) in subgroup Ia of HCC patients (P = 0.03 & P < 0.001 respectively). Cases of high survivin expression showed lower survival than cases of lower survivin expression in 1 year survival rates (9.6 &7.18 versus 11.8 & 11.6 months) for overall survival rate & disease free survival rate respectively. Finally, there was significant inverse correlation between survivin expression in tumorous tissues of HCC patients (subgroup Ia) and time lapsed till recurrence (P < 0.001) and time lapsed till death (P < 0.01).