الفهرس 
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Abstract
Hepatitis C is a global health problem, according to the World Health Organization (WHO), with 3-4 million people newly infected each year and 130-170 million individuals chronically infected. Hepatitis C-related liver disorders kill almost 350000 people each year. The data on the global prevalence are mostly based on HCV seroprevalence studies. People who have been infected with HCV are at risk for developing chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC).
A number of studies have revealed that single-nucleotide polymorphism (SNPs) could be related to liver carcinogenesis in definite populations. These studies highlighted differences within individual genomes that regulate DNA repair ,oxidative stress, , cell signaling, immune and inflammatory responses as hereditary predispositions toward hepatic-tumorigenesis and helped to explain the observed variances in HCC incidence risk.
RAGE (Receptor for Advanced Glycation End Products) is a multiligand immunoglobulin superfamily cell surface receptor. RAGE expression is typically low in most healthy adult tissues, but it is raised in pathological situations such diabetes, cardiovascular disease, Alzheimer’s disease, and cancer.
Activation of RAGE by various ligands has been shown to increase oxidative stress and, as a result, stimulate inflammatory, proliferative, angiogenic, fibrotic, thrombogenic, and apoptotic
responses in a variety of cell types via activation of intracellular signalling pathways. There is mounting evidence that activation of RAGE signalling pathways in the liver may have a role in the development of liver cancer.
Moreover, rs1800625 SNPs from the RAGE gene is exposed to be related to the progress of many malignancies, as lung cancer, kidney cancer, and oral cancer. Also, 63 bp deletion; a rare variant; is known to increase the transcriptional activity of RAGE.
In that way, this research aims to assess the effect of gene variations of RAGE on the progress of HCC caused by viral infection, and to observe an association of RAGE SNPs with the risk and progression of HCC.
90 HCV patients were included in this study , separated into 3 groups; group I included 30 HCV patients who developed Hepatocellular carcinoma (HCC). group II, include 30 HCV patients with liver cirrhosis. group III: include 30 chronic HCV patients without cirrhosis, in addition 20 healthy individuals as a control group (group IV). Patients suffering from any other disease were omitted from our study as infection with Schistosomiasis or other endemic disease.
The blood samples were collected from patients attending oncology diagnostic unit. The HCV cases were diagnosed by polymerase chain reaction (PCR) while the HCC ones were diagnosed by Alfa-fetoprotein (AFP) test in addition to computed tomography. Liver cirrhosis was diagnosed with abdominal sonography
We calculated the frequencies of distribution of RAGE gene polymorphism (rs 1800625) among the four studied groups. The results revealed that the majority of patients who developed HCC “group I” showed mutant genotype 83.3% in contrast to 16.7% who showed wild type of RAGE gene. Similar frequencies were observed in patients with liver cirrhosis “group II”, patients with chronic HCV virus who didn’t developed either hepatic cirrhosis or HCC. The mutant RAGE gene constitutes 80%, 73% and 70% in group II, III, and IV; respectively in contrast to 20%, 26.7% and 30% of wild type genotype.
Also the frequencies of the 63bp deletion mutation (-407 to - 345) in the 5ʼ flanking region of RAGE gene among the four studied groups were conducted. The results revealed that the majority of patients who developed HCC “group I” showed mutant genotype 86.7% in contrast to 13.3% who showed wild type of RAGE gene. Similar frequencies were observed in patients with liver cirrhosis “group II”, patients with chronic HCV virus who didn’t developed either hepatic cirrhosis or HCC. The mutant RAGE gene constitutes 66.7%, in contrast to 33.3% who showed wild type of RAGE gene in group II. On the other hand, the majority of cases in HCV group with cirrhosis (group III) showed wild genotype, the wild genotype constitutes 70% of cases in contrast to 30% who showed mutant genotype. Likewise, 60% of healthy groups (group IV) were of wild genotype in contrast to 40% of mutant genotype.
Moreover, the frequencies of different genotypes among the four investigated groups were calculated to determine the favourable and
unfavourable genotype of RAGE gene (C/T) polymorphism, the results revealed that the heterozygous TC genotype was the most frequent in the chronic HCV patients who develop HCC (group I) . In contrast, the homozygous CC genotype was the least frequent genotype in HCC group. Likewise, 58% of chronic HCV in patients who develop cirrhosis (group II) showed heterozygous TC genotype, however, equal percentage of patients 21% are of homozygous TT and CC genotype.
Concerning the chronic HCV group (group III), the heterozygous TC genotype is the major genotype, followed by homozygous genotype which constitutes 27%, meanwhile, homozygous CC genotypes was not detected in group III. For the healthy control, 50% of subjects showed homozygous TT genotype, followed by 43% of heterozygous TC genotype, however, the homozygous CC genotype was detected in only one subject.
We further, assessed and determined the type of mutation at 63bp flanking site which revealed that 85% of RAGE gene mutation in chronic HCV followed by HCC (group I), are of insertion genotype in contrast to 15% deletion mutation of RAGE 63bp mutation.
Likewise, 75% and 67% insertion mutation were observed in group II and group III, respectively. In contrast, it was found that the deletion mutation was more frequently distributed among healthy control group.
Also we calculated the serum levels of AFP, AST, ALT in HCC patients in homozygous TT genotype and in non TT genotypes
“TC/CC” to show the association between RAGE (C/T rs1800625) gene polymorphism and liver status, we found that the higher median level of AFP and AST was observed in patient who had non TT genotype in contrast to TT genotype.
Conclusion
In conclusion, the current study demonstrated that the RAGE gene polymorphism is significantly contributed to development of HCC in chronic HCV patients, however, it not associated with HCC progression. Accordingly, our data indicated the impact of RAGE gene variations on HCC development in HCV infected patients; however, the study has several limitations including: small sample size, potential heterogeneity, in term of the severity and subtype of liver cancer, variety of HCC-related clinical manifestations, such as diabetes, non-alcoholic fatty liver disease, and infection with HBV. Taken together, our results showed that SNP rs1800625 of RAGE gene causally contributes to an increased risk of HCC. In addition, an opposite association of rs1800625 was detected with the progression of HCC. These findings indicate a novel genetic predisposition to liver tumorigenesis.