View PDF Version - RePub - Erasmus Universiteit Rotterdam

UV-INDUCED SKIN CANCER AND MUTAGENESIS IN NER­
DEFICIENT MOUSE MODELS: COMPARISON WITH THE HUMAN
NER-SYNDROMES
XP A and XPC mice
In XP patients, the age of onset of non-melanoma skin tumors is reduced fronl 60
to 8 years of age [18]. Similarly, XPA and XPC mice show markedly induced
susceptibility to UV-induced skin cancer [1-4J. At a daily exposure of 80 J/m 2 in
hairless mouse background, the median latency time was reduced by a factor 4.2,
[rom 320 days in wild-type, to 74 days in XPA mice (UV 250-400 nm). A reduction
in approximately the same range was seen in XPC mice, suggesting that
transcription-coupled repair does not significantly protect against skin cancer, at
least in XPC mice (R. Berg, manuscript in prep.). Interestingly, a shift in tumor type
and mutational target genes was observed when hairless XPA mice were exposed to
a low daily dose of 32 J/m 2 instead of 80 J/m 2 [19]. Whereas mainly squamous cell
carcinomas (SCCs) were seen at the high UV -dose, a high frequency of papillomas
was found at the low dose. Analysis of genetic alterations in the different tumor
types revealed mutations in the H-ras gene in papillomas only and a remarkably low
number of p53 alterations in either tumor type, seemingly precluding a significant
role of the p53 tumor suppressor gene in skin tumorigenesis ofNER-defective mice.
Interestingly, in contrast to the absence of a prominent contribution of p53
mutations in SCC and papilloma's in the XPA mouse, Takeuchi and collaborators
[20J found p53 mutations in 48%, ofUV-induced skin tumors (mainly SCC) in UVexposed
XPA mice and a mutational fingerprint typical for UV and an NER defect.
Since the relationship ofp53 to genomic (in)stability is very important it is relevant
to consider this apparent discrepancy in more detail. Several explanations can be put
forward. First, the mice used in both studies were in a different genetic background.
Clear differences in the effect of p53 mutations on tumorigenesis have been noted
before in different mouse strains. Moreover, other parameters such as the efficacy of
inmmnesuppression could differ between the strains and influence the results.
Second, the Takeuchi study involved a dose >2 times that of de Vries et al.,
explaining also the different spectrum in the types of tumors observed. Moreover,
they allowed tumors to develop to a more advanced stage. Finally, Takeuchi cs used
microdissection to select specific tumor areas favoring detection of p53 mutations.
The above results can be rationalized by assuming that p53 mutations are a
relatively late event in UV-induced skin carcinogenesis. [20].
Studies with XPC-I-p53+1- mice show a further reduction in latency of
tumorigenesis after UV irradiation compared to XPC-I-p53+/+ mice [4]. Moreover,
XPC-I-p53+1- skin showed an aggravated response to UV light; in addition to
epidermal hyperplasia and hyperkeratosis the epidermis showed dysplasia, which
\vas even more pronounced in XPC-I-p53-1- animals. In line with this, tumors in
NER-deficient mouse models 33