Fine mapping reveals that promotion susceptibility locus 1 (Psl1) is a compound locus with multiple genes that modify susceptibility to skin tumor development.
Although it is well known that the majority of human cancers occur as the result of exposure to environmental carcinogens, it is clear that not all individuals exposed to a specific environmental carcinogen have the same risk of developing cancer. Considerable evidence indicates that common allelic variants of low-penetrance, tumor susceptibility genes are responsible for this interindividual variation in risk. We previously reported a skin tumor promotion susceptibility locus, Psl1, which maps to the distal portion of chromosome 9, that modified skin tumor promotion susceptibility in the mouse. Furthermore, Psl1 was shown to consist of at least two subloci (i.e., Psl1.1 and Psl1.2) and that glutathione S-transferase alpha 4 (Gsta4), which maps to Psl1.2, is a skin tumor promotion susceptibility gene. Finally, variants of human GSTA4 were found to be associated with risk of nonmelanoma skin cancer. In the current study, a combination of nested and contiguous C57BL/6 congenic mouse strains, each inheriting a different portion of the Psl1 locus from DBA/2, were tested for susceptibility to skin tumor promotion with 12-O-tetradecanoylphorbol-13-acetate. These analyses indicate that Psl1 is a compound locus with at least six genes, including Gsta4, that modify skin tumor promotion susceptibility. More than 550 protein-coding genes map within the Psl1 locus. Fine mapping of the Psl1 locus, along with two-strain haplotype analysis, gene expression analysis, and the identification of genes with amino acid variants, has produced a list of fewer than 25 candidate skin tumor promotion susceptibility genes.
Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712 jmangel@austin.utexas.edu John.digiovanni@austin.utexas.edu.
Joe M
JM
Angel
Department of Biology, Baylor University, Waco, Texas 76798.
Erika L
EL
Abel
Department of Animal Science, Texas A&M University, College Station, Texas 77843.
Penny K
PK
Riggs
Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712.
S Alex
SA
McClellan
Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712 Department of Nutritional Sciences, College of Natural Science, The University of Texas at Austin, Austin, Texas 78712 jmangel@austin.utexas.edu John.digiovanni@austin.utexas.edu.
John
J
DiGiovanni
D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D005810:Multigene Family; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012878:Skin Neoplasms / Q000235:genetics*
Psl1; complex trait genetics; compound locus; skin tumor promotion susceptibility locus; tetradecanoylphorbol acetate