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Identifier uch.med.phd//1998vaggeli
Title Ποιοτικές και ποσοτικές αλλαγές στην έκφραση των γονιδίων Ras στον καρκίνο της ουροδόχου κύστης του ανθρώπου
Alternative Title Qualitative and Quantitative Changes of Expression, of ras Family Oncogenes, in the Develpment of Human Bladder Cancer
Creator Vaggeli, Dimitra P
Abstract Cancer is a genetic disease, in which individual cells have been mutated, giving rise to uncontrolled proliferation. The identification of these mutated genes, that transform a normal cell to a cancer cell, has identified activated oncogenes, responsible for cellular aberration and inactivating oncosuppressor genes, while a further class of genes that is involved in the DNA repair has been demonstrated to correlate with a poor prognosis, when these genes are mutated. The aim of the present study was to evaluate the quantitative and qualitative changes of expression, of the ras family oncogenes, in the development of human bladder cancer. This approach exploited the use of Polymerase-Chain-Reaction analysis (PCR). The analysis revealed that, point mutations in codon 12 of the K-ras and N-ras oncogenes are rare events, while point mutations in codon 12 of the H-ras gene, was found at a significant level and may occur early in tumorigenesis of certain cancers of the urothelium Although the detection of point mutations in codon 12 of the ras genes did not elucidate the role of these genes in bladder cancer, the analysis of overexpression at the transcriptional level of the ras genes, indicated that the involvement of these genes is significant in the pathogenesis of bladder tumors. 73% of the samples expressed at least one member of ras family, indicating the frequent involvement of these genes in the disease. The three ras genes exhibited differential expression and we may postulate the presence of different regulator elements in the promotor sites of the three genes. These regulator regions are located in two polymorphic sites adjacent and within the H-ras1 proto-oncogene. The investigation of these two sites included the comparison between normal and tumor tissues from the same patient and detection of the genetic alterations that affected the regulation of H-ras gene expression. Futhermore, we found the 'linkage disequilibrium' between the two sites to be disturbed in the tumor samples, leading probably to a differential regulation of the H-ras alleles. The structural modifications occuring in repetitive sequences of the two polymorphic sites, have been associated with a mutator DNA-repair mechanism, suggesting an indirect way of the H-ras gene activation in bladder cancer. The loss of heterozygosity (LOH) analysis of the H-ras gene, revealed oncosuppressor-like activity in addition to the oncogenic action of the gene. When the H-ras gene has lost an allele, the structural modifications that occur at the microsatellite locus of the gene (mutations are caused by defective DNA-repair mechanism), may be expressed as prevalent, influencing the normal expression of this gene, in bladder tumor tissue, since in this region is located an 'anticancer element', which effects the H-ras proto-oncogene expression.
Issue date 1998-12-01
Date available 1999-06-22
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/b/9/3/metadata-dlib-1998vaggeli.tkl Bookmark and Share
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