Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility

The human TGFB1 gene is polymorphic, and genetic variants are associated with altered cancer risk. However, human genetic association studies have had variable outcomes because TGF beta 1 action is context-dependent. We used the murine skin model of chemical carcinogenesis in genetic linkage analysis of three independent Mus musculus NIH/Ola x (Mus spretus x M. musculus NIH/Ola)F-1 backcrosses, to identify a skin tumor susceptibility locus, Skts14, on proximal chromosome 7. Tgfb1 maps at the peak of linkage. The mouse Tgfb1 gene is polymorphic, resulting in cis-regulated differential allelic mRNA expression between M. spretus and M. musculus in F, mouse skin. This phenomenon is reflected in differential phospho-SMAD2 levels, downstream of TGF beta signaling, between these two mouse species. In normal F, mouse skin, the Tgfb1(SPR) allele is expressed at higher levels than the Tgfb1(NIH) allele, and this differential is accentuated by phorbol 12-myristate 13-acetate treatment. In benign F, papillomas, this imbalance is reversed, possibly by selection against expression of a hyperactive Tgfb1(SPR) allele in TGF beta growth-responsive tumors. We demonstrate that skin tumor susceptibility is altered by Tgfb1 gene dosage, but that manifestation of Tgfb1-linked skin tumor susceptibility in M. musculus NIH/Ola x (M. spretus x M. musculus NIH/Ola)F-1 backcross mice depends on interactions with another unlinked tumor modifying locus, Skts15, that overlaps Tgfbm3 on chromosome 12. These findings illustrate the power of complex genetic interactions in determining disease outcome and have major implications to the assessment of disease risk in individuals harboring variant TGFB1 alleles.