UV RADIATION, DNA DAMAGE, MUTATIONS AND SKIN CANCER - Environmental UV Radiation: Impact on Ecosystems and Human Health and Predictive Models - page 246

melanomagenesis. In further evidence, Chin et al. 52 demonstrated that Ink4a -/- mice in
which expression of a human mutant H-RAS G12V transgene was restricted to
melanocytes, developed melanomas. Although UV irradiation did not (yet) cause CM in
this mouse model, UV irradiation of hybrid Xiphophorus fish did cause CM 53 . UVA
radiation was surprisingly effective in this model, only about 10 fold less effective than
UVB radiation per unit radiant energy (J/m 2 ). It is, however, as yet unclear how UV
radiation affected CdknX/Ink4a or the Xmrk/ RTK mitogenic pathway. In the opossum
Monodelphis domestica UVB radiation appears to induce CM 54 , these tumors turned to
be particularly malignant when the UV radiation is given neonatally 55 . However, UVA
radiation did not induce malignant CM in this model 56 , only benign melanocytic
precursor lesions 57 . In a very recent study it was found that the UVB-induced CM from
these opossums carried UVB-like mutations in the CDKN2A homolog, and that only the
mutant allele was present and expressed in a metastatic cell line 58 .
4. Conclusions
From the data stated above it appears that at least a combination of an activated
oncogenic pathway and an inactivated tumor suppressor gene is needed in order for a
skin cancer to arise: in SCC it is possibly an activated RTK/RAS pathway in
combination with dysfunctional P53 tumor suppression, in BCC the Hedgehog pathway
with possibly dysfunctional P53, and in CM again possibly an activated RTK/RAS in
combination with inactivation of the INK4a locus. These combinations may be required,
but not necessarily sufficient for the development of a tumor. Additional oncogenic
events may be necessary.
Although the skin cancers appear to be related to UV radiation, the effect of UV
radiation is only unambiguously clear in point mutations of P53 in SCC and BCC. The
mutations found in the other relevant genes are of a wider variety, which may (in part)
be caused by solar UV radiation. Experiments are needed to clarify if and how UVB or
UVA radiations can affect other relevant genes. Overall, the data presently weigh most
heavily toward the carcinogenic effect of UVB radiation: the latest data on experimental
induction of CM in the opossum Monodelphis domestica are not indicative of any
important contribution of UVA radiation next to the dominant carcinogenicity of UVB
radiation
Acknowledgements. The author would like to thank the Dutch Cancer Society and the
European Commission for the financial support of their research groups.
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