Germline control of somatic Kras mutations in mouse lung tumors

ABSTRACT

Somatic KRAS mutations are common in human lung adenocarcinomas and areassociated with worse prognosis. In mice, Kras is frequently mutated in bothspontaneous and experimentally induced lung tumors, although the pattern ofmutation varies among strains, suggesting that such mutations are not random events.We tested if the occurrence of Kras mutations is under genetic control in two mouseintercrosses. Codon 61 mutations were prevalent, but the patterns of nucleotidechanges differed between the intercrosses. Whole genome analysis with SNPs in (A/J xC57BL/6)F4 mice revealed a significant linkage between a locus on chromosome 19and 2 particular codon 61 variants (CTA and CGA). In (AIRmax × AIRmin) F2 mice, therewas a significant linkage between SNPs located on distal chromosome 6 (around135 Mbp) and the frequency of codon 61 mutation. These results reveal the presenceof two loci, on chromosomes 6 and 19, that modulate Kras mutation frequency indifferent mouse intercrosses. These findings indicate that somatic mutation frequencyand type are not simple random events, but are under genetic control.