Genotype-specific Trp53 mutational analysis in ultraviolet B radiation-induced skin cancers in Xpc and Xpc Trp53 mutant mice

We have examined the mutational spectrum in the Trp53 gene from UVB radiati on-induced skin ranters in Trp53(+/+) and Trp53(+/-) mutant mice of all thr ee possible Xpc genotypes. Mutations were detected in exons 2-10 of the Trp 53 coding region in similar to 90% of >80 different skin cancers examined. In contrast to Trp53+/+ mice in which most mutations in the Trp53 gene were located in exons 5-8, the majority of the mutations in Trp53(+/-) mice wer e at other exons, We observed a high predilection for C --> T transition mu tations at a unique CpG site in codon 122 (exon 4) of the Trp53 gene in Xpc (-/-) Trp53(+/-) mice. This site is not part of a pyrimidine dinucleotide. Mutations at this codon, as well as in codons 124 and 210, were observed ex clusively in Xpc(-/-) or Xpc(+/-) mice. Mutations at the corresponding codo ns (127 and 213) in the human p53 gene have been reported in skin tumors fr om human patients with xeroderma pigmentosum. Hence, mutations at codons 12 2 (125), 124 (127), and 210 (213) may constitute signatures for defective o r deficient nucleotide excision repair in mice (humans). In Xpc-/- mice, th e majority of mutations ffcre located at C residues in CpG sites, in which the C is presumably methylated, A similar bias can be deduced from studies in human XP individuals.