Genetic mechanisms involving ultraviolet light in the development of cutaneous malignant melanoma

Major results ('deliverables') of our present activity in the MAUVE project on induction of melanocytic hyperplasia (moles/nevi) and tumors (melanomas): - 1 - "Intermittent overexposure to UVB radiation is effective in induction of nevi, possible precursor lesions of melanomas". (an important experimental substantiation of epidemiologic finding that irregular exposure leading to episodes of severe sunburns increases melanoma risk presumably by stimulating growth of melanocytic lesions in general) Notes: Sub - 1 - In contrast to expectation, overexposure of wild-type mice produced higher numbers of nevi than overexposure of XPA mice with a defect in repair of UVB-induced DNA damage.

The major results ('deliverables') of our activity in the MAUVE project concerning proliferation of pigment cells (melanocytes) in response to UV exposure: - 1 - "Intermittent overexposure to UVB radiation is most effective in stimulating melanocyte proliferation; fractionated sub-sunburn doses of UV are ineffective".(to be avoided because of possible simulation of melanocytic lesions; see next point). - 2 - "Long wavelength UVA1 radiation did not induce any proliferative response in our pigmented mice". - 3 - "Mice with a defect in repair of UVB-induced DNA damage (pyrimidine dimers) were found to be extremely sensitive to induction of melancyte proliferation". Notes: Sub - 1 -: this could explain the increase melanoma risk associated with intermittent sunburn exposures. Sub - 2 -: This shows that UVA1 has little indirect or direct effects on melanocytes capable of producing dark pigment (eumelanin). Sub - 3 - this stimulation is causally related to DNA damage as it is enhanced in DNA repair deficient XPA mice.

In the course of this project, a new combined SSCP/DGGE analysis method for mutation screening with high efficiency was developed. The results demonstrate that activating point mutations in N-ras and BRAF oncogenes are present in the majority of human melanoma precursors (premalignant melanocytic naevi). N-ras mutations occur most frequently in congenital naevi, BRAF mutations mainly in dysplastic naevi. These findings strongly suggest a mechanistic role for these gene alterations in the genesis of human malignant melanoma. Furthermore, the tumour suppressor genes apaf1 and chk2 was found to be mutated in malignant melanomas. In addition, evidence for functional deletions of p16 by point mutational mechanisms may indicate a causal role for reactive oxygen species (UV-A- and UV-B-induced) in melanoma development. These findings can support a better characterization of melanoma biopsies and help to improve grading and staging in melanoma diagnostics.

The main results ('deliverables) of our activity on induction of melanocytic hyperplasia (moles/nevi) and tumours (melanomas) are: - 1 - "Experimentally induced nevi in Ink4a/Arf knock out mice do not, or only rarely, progress to melanoma". (Implying that essential oncogenic alterations, gene mutations, may still be lacking in these UV-induced nevi). - 2 - " The dark pigment (eumelanin) in the mice is likely to protect very strongly against melanoma initiation/progresssion". Notes: Sub - 1 - dysfunctional INk4a/Arf is related to familial melanoma, and expression of the p16/Ink4a protein is commonly low in melanoma, but surprisingly, the nevi that arise with a dysfunction in these proteins do not show a high rate of progression toward malignant melanoma. In micro-dissections of the nevi will check for mutations in the oncogenes Braf and N- (K-. H-) ras, commonly found mutated in human nevi and melanocytes. Sub - 2 - A possibly low level of UV-induced genotoxic damage to the melanocytes containing eumelanin in our mice explains why we did not see a high rate of induction of melanoma, in contrast to recent experiments ran by others who worked with transgenic albino mice who did develop amelanotic melanoma.

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