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Genetic effects of increases in solar ultraviolet radiation and predicted consequences for human skin cancer incidence

Objective

i) To develop techniques for monitoring the load of cancer related mutations in non-neoplastic human skin,
ii) To improve the level of understanding of the role of UV-B in the aetiology of cutaneous malignant melanoma, with particular emphasis on damage to oncogenes and tumour suppressor genes.

As a result of depletion of stratospheric ozone, the level of ultraviolet B (UVB) radiation to which human populations are exposed is likely to increase, both in the Northern and Southern hemispheres. UVB damages deoxyribonucleic acid (DNA) in human skin cells leading to genetic mutations, some of which occur in genes (oncogenes and tumour suppressor genes) critical for regulating cell proliferation. One potentially serious human consequence of this increase in UVB is therefore likely to be a rising incidence of all forms of skin cancer. A highly sensitive method has been developed for quantifying mutations in the p53 tumour suppressor gene in apparently normal sun exposed skin. This technique, based on the use of polymerase chain reaction (PCR) will be used to study ultraviolet (UV) specific cancer related DNA damage in human populations in different geographical locations, of varying natural pigmentation, and skin cancer incidence. A consistently higher incidence of mutations at codons 245, 247 and 248 (sites known to result in loss of the tumour suppressive function of the gene) has been observed in the sun exposed skin.

Chromosome transfer technology has been employed in an effort to determine the genetic lesions responsible for the induction of cutaneous malignant melanoma in humans. As a result of this work, a gene has been assigned to a relatively small region of chromosome 9 (9p21) which has pronounced anti-proliferative activity in human melanoma cells and a number of fibroblast cell types. This region is close to (or possibly coincident with) the human familial melanoma susceptibility locus, and is also lost at an early stage in the majority of sporadic melanomas.

In additional studies on the genetics of human melanoma, UV related mutations have been characterized in ras oncogenes and the p53 tumour suppressor gene in melanoma samples. A significant association has been found between the presence of N-ras mutations and a specific, highly aggressive, sub-type of melanoma (nodular malignant melanoma). The precise based changes in the genes have been determined. All of these studies are continuing.
As a result of depletion of stratospheric ozone, the level of UV-B radiation to which human populations are exposed is likely to increase, both in the Northern and Southern hemispheres. UV-B damages DNA in human skin cells leading to genetic mutations, some of which occur in genes (oncogenes and tumour suppressor genes) critical for regulating cell proliferation. One potentially serious human consequence of this increase in UV-B is therefore likely to be a rising incidence of all forms of skin cancer.

A highly sensitive method has been developed for quantifying mutations in the p53 tumour suppressor gene in apparently normal sun-exposed skin. This technique, based on the use of polymerase chain reaction (PCR) will be used to study UV-specific cancer-related DNA damage in human populations in different geographical locations, of varying natural pigmentation, and skin cancer incidence.

In parallel with the human skin study, considerable effort will be devoted to the identification of novel key genes involved in the genesis of malignant melanoma (which carries a relatively poor prognosis and for which the link with UV exposure is not quite as clear-cut as with squamous cell and basal cell carcinoma). Particular emphasis will be placed on: (i) the use of microcell-mediated monochromosomal transfer techniques and PCR-based sequence tagged site (STS) mapping to pinpoint suspected tumour suppressor genes on chromosomes 1, 6 and 9 as a prelude to molecular cloning, and (ii) the molecular analysis of ras oncogene and p53 suppressor mutations in skin cancers in a search for specific mutational footprints diagnostic of UV-B involvement.

Collectively, these studies should generate persuasive (i.e. direct molecular) evidence for a dominant role for UV in human skin carcinogenesis and, moreover, allow cancer-associated mutations to be monitored in human populations at risk before cancers have developed. The availability and promulgation of credible scientific information about the increasing hazards of sun exposure should permit comprehensive skin cancer prevention programmes to be mounted more effectively.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Brunel University
Address

UB8 3PH Uxbridge
United Kingdom

Participants (2)

Centre International de Recherche sur le Cancer
France
Address
150 Cours Albert Thomas
69372 Lyon
Universität Rostock
Germany
Address
Universitätsplatz 2-4
18051 Rostock