The Car-R outbred mouse line was phenotypically selected for high resistance to two-stage skin tumorigenesis. In the present study we tested the hypothesis that a subset of genetic loci responsible for resistance to skin tumorigenesis of Car-R mice might also inhibit lung tumorigenesis. Skin and lung tumorigenesis were induced in groups of Car-R, SWR/J, (SWR/JxCar-R)F1 and SWR/Jx(SWR/JxCar-R) backcross mice by i.p. urethane initiation and skin TPA promotion. Car-R mice showed a much lower susceptibility to both skin and lung tumorigenesis as compared to SWR/J mice, which are susceptible to both lung and skin tumorigenesis. The Car-R-inherited genome significantly inhibited both skin and lung cancer development in the F1 progeny of Car-R with SWR/J mice. In the backcross population, skin and lung tumor phenotypes showed a statistically significant correlation, indicating that a subset of the cancer resistance alleles, which segregated in the Car-R line during selection for resistance to skin carcinogenesis, provides resistance to both skin and lung tumorigenesis. © 2002 Wiley-Liss, Inc. Key words: cancer modifiers; genetic susceptibility; inherited predisposition; Kras2 linkage disequilibrium; lung neoplasm; Pthlh Non-inbred carcinogenesis-resistant (Car-R) and carcinogensusceptible (Car-S) mouse lines were generated by phenotypic selection for resistance and susceptibility, respectively, to 2-stage skin carcinogenesis, starting from a cross of 8 inbred strains (A, BALB/c, C57BL/6, CBA, DBA/2, P, SJL and SWR). 1,2 The Car mice interline difference in susceptibility is Ͼ100-fold. 3 Tumor susceptibility and resistance in the Car lines were initially considered skin tissue-specific, because there was no interline difference in sarcoma induction by subcutaneous injection of chemical carcinogens. 4 In our present study, we tested the hypothesis that Car-R mice carry cancer resistance loci that inhibit susceptibility to both skin and lung tumorigenesis. Tumors were initiated in SWR/J mice, which are highly susceptible to both lung and skin cancer 3 and in Car-R and (SWR/JxCar-R)F1 mice using urethane, a multi-organ carcinogen that can initiate both lung and skin tumorigenesis. 5,6 Analysis of urethane-initiated and TPA-promoted Car-R, SWR/J and (SWR/JxCar-R)F1 mice revealed resistance to both skin and lung carcinogenesis in the Car-R line and F1 hybrids, showing that the genetic resistance of Car-R mice to both tumor types is dominant over the susceptibility of the SWR/J strain. Linkage disequilibrium (LD) and haplotype analyses showed that Car-R mice carry the Pulmonary adenoma susceptibility 1 (Pas1 s ) allele despite their resistance to lung tumorigenesis. The Pas1 s allele is carried by A/J and SWR/J mice and is dominant in crosses between A/J and C3H/He or C57BL/6 mice. 7,8 Resistance alleles, however, carried by some mouse strains (e.g., M. spretus, BALB/c, SM/J) at pulmonary adenoma resistance (Par) loci inhibit Pas1-mediated susceptibility to lung tumorigenesis in a dominant or co-dominant way. 9 -11 Skin an...