Cancer predisposition in mutant mice defective in multiple genetic pathways: uncovering important genetic interactions

Mouse models that mimic the human skin cancer-prone disease xeroderma pigme ntosum (XP) provide an useful experimental system with which to study the r elationship between the DNA repair process of nucleotide excision repair (N ER) and ultraviolet- (UV) induced skin carcinogenesis. We have generated Xp c mutant mice and documented their deficiency in the process of NER of UV-i nduced DNA damage. Xpc mutant mice are highly predisposed to UV-B radiation -induced skin cancer, both in the homozygous and the heterozygous state. Th e combination of Xpc and Trp53 mutations enhances this predisposition and a lters the tumor spectrum observed in single mutant mice. These results sugg est a synergism between NER and the function of Trp53 in suppression of can cer. We have examined the mutational spectrum in the Trp53 gene from skin c ancers in Trp53(+/+) and Trp53(+/-) mice of all three Xpc genotypes and hav e found evidence for signature mutations associated with defective NER. In addition, we have demonstrated that Xpc mutant mice are highly predisposed to the induction of lung and liver cancers by treatment with 2-acetylaminof luorene (2-AAF) and N-OH-2-AAF. By combining the Xpc mutation with other mutations in genes involved in rep air of DNA damage we have identified additional genetic interactions import ant in carcinogenesis. The mouse Apex gene is a critical component of the b ase excision repair (BER) pathway as well as the redox regulation of transc ription factors important in growth control and the cellular response to DN A damage. By combining mutations in Xpc, Trp53 and Apex we have obtained ge netic evidence for a functional interaction between Apex and Trp53 which pr obably involves the activation of the Trp53 protein by Apex. Mutations in t he mismatch repair (MMR) gene Msh2 also influence the carcinogenesis observ ed in Xpc Trp53 mutant mice. Our results demonstrate that multiple repair p athways operate in prevention of tumor formation. (C) 2001 Elsevier Science B.V. All rights reserved.