Allele-specific Hras mutations and genetic alterations at tumor susceptibility loci in skin carcinomas from interspecific hybrid mice.

We have investigated the effects of germ-line variants that influence skin tumor susceptibility loci on the patterns of somatic genetic alterations in mouse skin cancers. Using a two-stage skin carcinogenesis model, we previously identified at least 13 skin tumor susceptibility (Skts) loci in a large interspecific F1 backcross [(NIH/Ola x M. spretus) x NIH/Ola] study. In this report, we describe the analysis of allele-specific alterations at these loci in skin tumors from the same backcross animals. The mouse Hras gene, located close to Skts2 on chromosome 7, had specific activating mutations in the Mus musculus allele in 23 of 26 carcinomas. In all cases, tumors with Hras mutations also showed specific imbalance of chromosome 7 markers that favored the chromosome carrying the mutant allele. Allele-specific quantitative microsatellite analysis was also carried out, using DNA from 62 carcinomas from (NIH/Ola x M. spretus) x NIH/Ola mice. Frequent allelic imbalance was detected at five additional tumor-susceptibility loci on chromosomes 4, 6, 7, 9, and 16 (Skts7, Skts12, Skts1, Skts6, and Skts9, respectively). At all except Skts7, we found loss of the allele inherited from the resistant strain or amplification of the allele from the susceptible strain. We conclude that polymorphisms in some low-penetrance tumor modifier genes are reflected in the pattern of somatic alterations in tumors. Analysis of such allele-specific changes in tumors may facilitate the identification of functional germ-line variants that control tumor susceptibility.