UV RADIATION, DNA DAMAGE, MUTATIONS AND SKIN CANCER - Environmental UV Radiation: Impact on Ecosystems and Human Health and Predictive Models - page 243

was found to yield many T to G transversions in the aprt gene of CHO cells 15 . An
explanation could be the mispairing of A to an 8-oxo-G that was formed in the
nucleoside pool instead of the genomic DNA 16 .
More recent experimental studies have clearly shown that UV radiation can also
cause crude chromosomal aberrations in mammalian cells, such as detected by micro-
nucleï formation, i.e., UV radiation is clastogenic 17-18 . It is, however, unknown which
primary DNA lesions are responsible for these gross effects on chromosomes.
3. Oncogenes and tumor suppressor genes in skin cancer
In the cell there are various potential oncogenes and tumor suppressor genes that
often play their roles in more than one signaling pathway, rather they function in
signaling networks. UV radiation appears to be related to 3 types of skin cancer: the
most common one, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and
the most malignant one, cutaneous melanoma (CM). The question arises which genes
and pathways are disrupted by UV radiation in which of these cancers.
UV mutations in P53 from BCC and SCC
The P53 tumor suppressor gene is found to be mutated in a majority of human
cancers. The p53 protein is therefore an apparently vulnerable part of the cell's signaling
network: p53 plays a pivotal role in several signaling pathways related to DNA damage
and expression of oncogenes 19 . Nuclear p53 expression is elevated after UV irradiation,
and following a genotoxic insult p53 is involved in cell cycle arrest (late G1 and G2/M),
apoptosis ('programmed cell death') and DNA repair. In SCC (about 90%) and BCC
(>50%), from the US white population the P53 gene appears to bear point mutations
with the exact features of UVB-induced point mutations, i.e., associated with di-
pyrimidinic sites, mostly C to T transitions and 5-10% CC to TT tandem mutations 20-21 .
Evidently, the P53 gene is also a target in UV carcinogenesis, which has been
extensively confirmed in mouse experiments 22-23 . In line with this finding, it is found
that the wavelength dependency of the induction of SCC closely parallels that of the
induction of UV-induced DNA damage (pyrimidine dimers) in the skin, especially over
the UVB and UVA2 bands 24-26 .
Experiments with hairless mice show that clusters of epidermal cells with mutant
p53 occur long before SCC become visible 27 ; such clusters of mutant p53 have also
been found in human skin 28-29 . Dysfunctional p53 is likely to affect protective responses
against DNA damage and oncogenic signaling. Hence, the early occurrence of
P53 mutations may cause genomic instability and thus facilitate further carcinogenic
progression. The frequency of p53-mutant cell clusters in the skin may be a direct
indicator of skin cancer risk 30 .
A mutation in the P53 gene is clearly not enough to cause BCC or SCC. At the
very least some oncogenic pathway has to be activated; e.g., a growth-stimulating
pathway which normally starts with the activation (oligomerization) of a receptor
tyrosine kinase (RTK), e.g. EGF-R, at the cell membrane, and is further mediated
through proteins like RAS into the cell cytoplasm from which transcription factors are
finally activated. Activating RAS mutations have been reported in a minority of SCC