Genetic and epigenetic evaluation of the candidate genes in human hepatocellular carcinomas

Ankara : The Department of Molecular Biology and Genetics and the Institute of Engineering and Science of Bilkent University, 2010.Thesis (Ph. D.) -- Bilkent University, 2010.Includes bibliographical references leaves 173-199.Hepatocellular carcinoma (HCC) is the fifth most-common cancer and the third most common cause of cancer related mortality worldwide. HCC is also the most common type of liver cancer. Hepatocarcinogenesis is a multistep process that is not completely understood until today. In this study, we genetically and epigenetically evaluated candidate genes and molecular pathways which may act in hepatocarcinogenesis. The RAS/RAF/MAPK pathway was genetically investigated and no mutation was described in HCC cell lines for the genes MEK1 (MAP2K1), MEK2 (MAP2K2), ERK1 (MAPK3), ERK2 (MAPK1) and PTP 11 (SHP2). TP53 pathway is also a common target for inactivation during liver carcinogenesis. Our analysis indicated that the presence of the MDM2-SNP309 G allele is inversely associated with the presence of somatic TP53 mutations. This finding suggests that the MDM2-SNP309 G allele may functionally replace TP53 mutations, and in addition to known etiological factors, may be partly responsible for differential HCC prevalence. Epigenetic silencing of SIP1 gene in HCC together with its reduced mRNA and protein level in tumors relative to normal liver tissue indicated SIP1 as a potential tumor suppressor role. Inconsistent with previously published findings in other types of cancers, our results showed for the first time that PTPRD gene is epigenetically downregulated and mutated in liver cancers. Among other candidates our results suggest; FBXL11, TUBA3C, TPTE2, IQSEC1, MIPOL1, CHUK, MCL1, MAGI-2 and PTPRCAP genes are involved in hepatocarcinogenesis.Acun, TolgaPh.D