title: Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility.
abstract: 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 TGFbeta1 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)F1 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 F1 mouse skin. This phenomenon is reflected in differential phospho-SMAD2 levels, downstream of TGFbeta signaling, between these two mouse species. In normal F1 mouse skin, the Tgfb1SPR allele is expressed at higher levels than the Tgfb1NIH allele, and this differential is accentuated by phorbol 12-myristate 13-acetate treatment. In benign F1 papillomas, this imbalance is reversed, possibly by selection against expression of a hyperactive Tgfb1SPR allele in TGFbeta 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)F1 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.
authors.affiliation: Cancer Research Institute, Comprehensive Cancer Center, Department of Biochemistry, University of California, San Francisco, CA 94143-0875, USA.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Elise F
authors.initials: EF
authors.lastname: Saunier
authors.forename: John P
authors.initials: JP
authors.lastname: de Koning
authors.forename: Margaret M
authors.initials: MM
authors.lastname: McKinnon
authors.forename: Mamie Nakijama
authors.initials: MN
authors.lastname: Higgins
authors.forename: Kathy
authors.initials: K
authors.lastname: Nicklas
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Yang
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Akhurst
mesh_terms: D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006720:Homozygote; D051379:Mice; D011110:Polymorphism, Genetic; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D016212:Transforming Growth Factor beta