Objetivo Primary Objective To provide new scientific information, of use to the Commission, concerning the relative importance of different wavelengths of ultraviolet (UV) light in the induction of the three major forms of human skin cancer. Key Subsidiary Objectives (i) To determine the role of indirect DNA damage (e.g. that caused by reactive oxygen radicals) in skin carcinogenesis, (ii) to develop a sensitive molecular screening method suitable for monitoring the accumulation of cancer-related mutations induced by UV in normal human skin, (iii) to use newly discovered human skin cancer markers, in particular the CDKN2A (p16) suppressor gene and the cell immortality enzyme telomerase, to improve understanding of the relative contribution of UV-A and UV-B effects in the induction of malignant melanoma.Experimental Approaches In order to achieve the set goals the project work will involve the use of a wide variety of state-of-the-art molecular biological methods, including the polymerase chain reaction (PCR), cancer gene cloning and sequencing, and the highly sensitive (PCR-based) 'TRAP' assay (for measuring functional telomerase in skin tumours). In addition, animal models (i.e. hairless mice) will be employed to construct detailed action spectra for UV skin carcinogenesis. A new generation of assays for measuring UV-induced mutations in the p53 tumour suppressor gene in intact human skin will be developed. Expected Achievements Studies with hairless mice will provide a detailed description of the wavelength dependency of UV carcinogenesis, particularly with regard to UV-A and UV-B contributions, and of the induced mutational spectrum in UV-induced tumours. The degree of involvement of oxidative damage will have been determined. A new generation of highly sensitive PCR-based assays for quantifying UV-B-induced (direct) mutations in normal human skin will be available to monitor the accumulation of p53 mutant cells in sun-exposed versus protected normal human skin samples. The role of direct DNA damage induced by UV-B exposure in non melanotic skin cancer induction will be better understood. Other molecular studies will permit a scientifically sound statement to be made regarding the importance of loss of function of the CDKKN2A tumour suppressor gene in human melanoma, and will furnish knowledge as to the extent to which the various wavelengths of UV are responsible for mutational and/or epigenetic silencing of CDKN2A. The precise timing of telomerase activation during melanoma and non-melanoma skin carcinogenesis, together with the involvement of UV-A and UV-B in telomerase induction, will be known. Additional skin tumour suppressor genes located on human chromosome-9 will have been identified and will form the basis of future molecular epidemiological investigations of UV involvement in human skin cancer. Ámbito científico natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologyskin cancermelanomanatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programa(s) FP4-ENV 2C - Specific programme of research and technological development in the field of environment and climate, 1994-1998 Tema(s) 01020202 - Alteration of processes as a result of UV-B radiation Convocatoria de propuestas Data not available Régimen de financiación CSC - Cost-sharing contracts Coordinador Brunel University Aportación de la UE Sin datos Dirección UB8 3PH Uxbridge Reino Unido Ver en el mapa Coste total Sin datos Participantes (5) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo Centre International de Recherche sur le Cancer Francia Aportación de la UE Sin datos Dirección 150 cours Albert Thomas 69372 Lyon Ver en el mapa Coste total Sin datos Rijksuniversiteit Utrecht Países Bajos Aportación de la UE Sin datos Dirección 100,Heidelberglaan 3508 GA Utrecht Ver en el mapa Coste total Sin datos Stiftung Deutsches Krebsforschungszentrum Alemania Aportación de la UE Sin datos Dirección Im Neuenheimer Feld 280 69120 Heidelberg Ver en el mapa Coste total Sin datos UNIVERSITAET KOELN Alemania Aportación de la UE Sin datos Dirección Joseph-Stelzmann-Srasse 52 50931 KOELN Ver en el mapa Coste total Sin datos Universität Rostock Alemania Aportación de la UE Sin datos Dirección Universitätsplatz 2-4 18051 Rostock Ver en el mapa Coste total Sin datos
