Polygenic resistance to mouse pulmonary adenomas

Susceptibility to urethan-induced pulmonary adenomas (PA) in mice is under polygenic control. To analyze these traits in detail, we generated a set of recombinant inbred (RT) mouse strains, called SMXA, front an intercross be tween PA-susceptible A/J and resistant SM/J, and established a strain distr ibution pattern (SDP) table of 158 marker loci for SMXA RI strains. From th e SDP table, it was possible to estimate the allele for 4 known PA suscepti bility (Pas) loci in all members of SMXA RI strains. We compared combinatio ns of Pas loci alleles with the data of number of PA induced by urethan. On e of the RI strains, SMXA24, showed extremely low PA numbers, whereas they had the A/J-derived alleles at all 4 Pas loci. F1 hybrids of SMXA24 and A/J developed as few PA as SMXA24 on exposure to urethan. To confirm the hypot hesis that SMXA24 has dominant PA resistance gene(s), we examined a backcro ss generation to A/J for multiplicity of PA. A preliminary genome scan foll owed by quantitative trait locus analysis revealed two resistance loci, one on mouse chromosome 11 (MMU11) (logarithm of odds [LOD] score 4.35) and an other on MMU12 (LOD score 6.47). They were named Par1 and Par3, respectivel y. Both loci were epistatic to Pas1, the major susceptibility loci on MMU6. We next asked if such dominant resistance loci play some role in human lun g cancer by studying possible loss of heterozygosity (LOH) at syntenic chro mosomal segments in 79 human lung cancers, including 30 adenocarcinomas, 25 squamous cell carcinomas (SQ), and 24 small cell carcinomas (SCC). The map positions of Par1 and Par3 correspond to human 17q11-23 and 14q11-24. Of 3 0 adenocarcinomas, LOH was found in 53% at 17q and in 30% at 14q. For both SQ and SCC, LOH in 17q were about 10%, but LOH in 14q was about 30% to 42%. Therefore, a gene in 17q seemed to be selective for adenocarcinomas, proba bly at the level of the target cell. In contrast, another gene in 14q affec ted all 3 types of lung carcinomas, suggesting it is related to the progres sion of lung tumors in general. A comparative approach may provide useful i nformation for understanding human cancers.