Multigenic nature of the mouse pulmonary adenoma progression 1 locus

In an intercross between the SWR/J and BALB/c mouse strains, the pulmonary adenoma progression 1 (Papg1) locus on chromosome 4 modulates lung tumor size, one of several measures of lung tumor progression. This locus has not been fully characterized and defined in its extent and genetic content. Fine mapping of this and other loci affecting lung tumor phenotype is possible using recombinant inbred strains.

A population of 376 mice, obtained by crossing mice of the SWR/J strain with CXBN recombinant inbred mice, was treated with a single dose of urethane and assayed for multiplicity of large lung tumors (N2lung). A genome-wide analysis comparing N2lung with 6364 autosomal SNPs revealed multiple peaks of association. The Papg1 locus had two peaks, at rs3654162 (70.574 Mb, -logP=2.8) and rs6209043 (86.606 Mb, -logP=2.7), joined by an interval of weaker statistical association; these data confirm the presence of Papg1 on chromosome 4 and reduce the mapping region to two stretches of ~6.8 and ~4.2 Mb, in the proximal and distal peaks, respectively. The distal peak included Cdkn2a, a gene already proposed as being involved in Papg1 function. Other loci possibly modulating N2lung were detected on chromosomes 5, 8, 9, 11, 15, and 19, but analysis for linkage disequilibrium of these putative loci with Papg1 locus suggested that only those on chromosomes 11 and 15 were true positives.

These findings suggest that Papg1 consists, most likely, of two distinct, nearby loci, and point to putative additional loci on chromosomes 11 and 15 modulating lung tumor size. Within Papg1, Cdkn2a appears to be a strong candidate gene while additional Papg1 genes await to be identified. Greater knowledge of the genetic and biochemical mechanisms underlying the germ-line modulation of lung tumor size in mice is relevant to other species, including humans, in that it may help identify new therapeutic targets in the fight against tumor progression.