%0 Journal Article %J Carcinogenesis %D 2012 %T Independent genetic control of early and late stages of chemically induced skin tumors in a cross of a Japanese wild-derived inbred mouse strain, MSM/Ms. %A Okumura, Kazuhiro %A Sato, Miho %A Saito, Megumi %A Miura, Ikuo %A Wakana, Shigeharu %A Jiang-Hua Mao %A Miyasaka, Yuki %A Kominami, Ryo %A Wakabayashi, Yuichi %K 9,10-Dimethyl-1,2-benzanthracene %K Animals %K Carcinogens %K Crosses, Genetic %K Female %K Genetic Linkage %K Japan %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Inbred Strains %K Mice, Knockout %K Papilloma %K Skin Neoplasms %K Tetradecanoylphorbol Acetate %K Tumor Suppressor Protein p53 %X

MSM/Ms is an inbred mouse strain derived from a Japanese wild mouse, Mus musculus molossinus. In this study, we showed that MSM/Ms mice exhibit dominant resistance when crossed with susceptible FVB/N mice and subjected to the two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA)/ 12-O-tetradecanoylphorbol-13-acetate (TPA). A series of F1 backcross mice were generated by crossing p53(+/+) or p53(+/-) F1 (FVB/N × MSM/Ms) males with FVB/N female mice. These generated 228 backcross animals, approximately half of which were p53(+/-), enabling us to search for p53-dependent skin tumor modifier genes. Highly significant linkage for papilloma multiplicity was found on chromosomes 6 and 7 and suggestive linkage was found on chromosomes 3, 5 and 12. Furthermore, in order to identify stage-dependent linkage loci we classified tumors into three categories (<2mm, 2-6mm and >6mm), and did linkage analysis. The same locus on chromosome 7 showed strong linkage in groups with <2mm or 2-6mm papillomas. No linkage was detected on chromosome 7 to papillomas >6mm, but a different locus on chromosome 4 showed strong linkage both to papillomas >6mm and to carcinomas. This locus, which maps near the Cdkn2a/p19(Arf) gene, was entirely p53-dependent, and was not seen in p53 (+/-) backcross animals. Suggestive linkage conferring susceptibility to carcinoma was also found on chromosome 5. These results clearly suggest distinct loci regulate each stage of tumorigenesis, some of which are p53-dependent.

%B Carcinogenesis %V 33 %P 2260-8 %8 2012 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22843548?dopt=Abstract %R 10.1093/carcin/bgs250