Genome-wide identification of genetic modifiers of Pak1-dependent skin tumor susceptibility in mice.

Pak1, a serine/threonine kinase, plays dual roles during the tumor progression and immune response. Unfortunately, the genetic modifiers underlying the resistance caused by Pak1 deficiency in CD11c-positive immune cells have been poorly defined so far. To adequately address this gap, we conducted a forward genetic screen using Cd11cCre-Pak1fl/+ F1 backcross mice (n=182). GRAS-Di-based genome-wide genotyping has identified 14,053 high-confidence markers, and we analyzed them by taking advantage of the principal component-adjusted generalized linear models (GLMs). Among the nine candidates of genome-wide significant Pak1 modifier loci (Pm1-Pm9) associated with tumor susceptibility, Pm1 on chromosome 5 showed the earliest and strongest association with the stages of papilloma and carcinoma. Intriguingly, epistasis analysis revealed that Pm3 on chromosome 4 attenuates the tumor-promoting effect of Pm1 in an allele-dependent manner, raising a possibility that the immune regulators modulate tumor susceptibility in Pak1-reduced immune compartment. Taken together, our present findings delineate a genetic framework implicated in Pm1/Pm3 axis during Pak1-reduced, skin carcinogenesis driven by immune response.