UV RADIATION, DNA DAMAGE, MUTATIONS AND SKIN CANCER - Environmental UV Radiation: Impact on Ecosystems and Human Health and Predictive Models - page 244

and BCC to various percentages 31-32 . These activating mutations are restricted to the
codons 12, 13 and 61, and are not specific of UV radiation. The RAS-pathway may be
involved in SCC and BCC, but it is not usually effected through genetic changes in the
RAS family of genes .
BCC and the PTCH gene
Patients with Gorlin syndrome, or basal cell nevus syndrome (BCNS), suffer
from multiple, familial BCC. This genetic trait was traced to mutations in the PTCH
gene 33 . Next to frequent loss of one of the parental alleles (i.e. loss of heterozygosity,
LOH) at this locus, many sporadic - non-familial - BCC showed mutations in the
(remaining) PTCH allele 34 : 12 out of 37 tumors in SSCP screening, and 9 of these
tumors showed LOH of PTCH . (The SSCP was apparently not sensitive enough as two
tumors without variant SSCP or LOH were both found to have inactivating mutations.)
Seven of 15 mutations occurred at di-pyrimidinic sites and were C to T transitions
(among which 2 CC to TT tandem mutations), and could, therefore, have been caused
by UVB radiation.
The PTCH gene is a serpentine-like receptor woven through the cell membrane.
Extra-cellular 'Sonic Hedgehog' (SHH) protein couples to PTCH which triggers a
pathway that ultimately activates the transcription factor GLI1, which induces
epidermal hyperplasia 35 , and which is expressed in almost all BCC 36 . Skin grafts of the
SHH-transgenic keratinocytes onto immune-deficient mice show the specific histologic
features of BCC 37 . This indicates that activation of this Sonic Hedgehog pathway is
essential to the formation of BCC. This has been confirmed in transgenic mouse strains.
Ptc (murine homolog of PTCH ) heterozygous knockout mice 38-39 develop
microscopically detectable follicular neoplasms resembling human trichoblastomas and
40% develop BCC-like tumors after 9 months. Upon exposure to ionizing or UVB
radiation the trichoblastomas and BCC occur earlier, and increase in size and numbers 40 .
The trichoblastomas and BCC show frequent loss of the wildtype Ptc allele, and all the
ones tested (n=12) showed expression of Gli1 (SCC, n=2, did not). Two BCC out of 5
UV-induced trichoblastoma/BCC-like tumors carried p53 mutations (3 in total, 2 C to T
and 1 C to G). These experimental data show that UV radiation can play an important
role in causing or enhancing the development of BCC. Next to the induction of p53
mutations, UV radiation could exert a more direct effect on the Sonic Hedgehog
pathway by enhanced loss of the wildtype Ptc gene and/or possible mutation of this
gene.
Melanoma and INK4a
Some familial CM are linked to the “multiple tumor suppressor” ( MTS1 ) gene 41
(designated CDKN2A in the human genome project). It is also named INK4a 42 after the
original finding that its product p16 INK4a becomes associated with cyclin dependent
kinases upon transformation of human fibroblasts by SV40 virus, and acts as an
inhibitor of CDK4 and CDK6. CDK4 is thus prevented from phosphorilating pRB and
activating the E2F-1 transcription factor. An alternative reading frame in INK4a codes