title: Mouse pulmonary adenoma susceptibility 1 locus is an expression QTL modulating Kras-4A.
abstract: Pulmonary adenoma susceptibility 1 (Pas1) is the major locus responsible for lung tumor susceptibility in mice; among the six genes mapping in this locus, Kras is considered the best candidate for Pas1 function although how it determines tumor susceptibility remains unknown. In an (A/J × C57BL/6)F4 intercross population treated with urethane to induce lung tumors, Pas1 not only modulated tumor susceptibility (LOD score = 48, 69% of phenotypic variance explained) but also acted, in lung tumor tissue, as an expression quantitative trait locus (QTL) for Kras-4A, one of two alternatively spliced Kras transcripts, but not Kras-4B. Additionally, Kras-4A showed differential allelic expression in lung tumor tissue of (A/J × C57BL/6)F4 heterozygous mice, with significantly higher expression from the A/J-derived allele; these results suggest that cis-acting elements control Kras-4A expression. In normal lung tissue from untreated mice of the same cross, Kras-4A levels were also highly linked to the Pas1 locus (LOD score = 23.2, 62% of phenotypic variance explained) and preferentially generated from the A/J-derived allele, indicating that Pas1 is an expression QTL in normal lung tissue as well. Overall, the present findings shed new light on the genetic mechanism by which Pas1 modulates the susceptibility to lung tumorigenesis, through the fine control of Kras isoform levels.
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Dassano
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Colombo
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Trincucci
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Frullanti
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Galvan
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pettinicchio
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.affiliation: Laboratory of Immunogenetics, Instituto Butantan, Saõ Paulo, Brazil.
authors.forename: Andrea
authors.initials: A
authors.lastname: Borrego
authors.affiliation: Laboratory of Immunogenetics, Instituto Butantan, Saõ Paulo, Brazil.
authors.forename: Olga Célia
authors.initials: OC
authors.lastname: Martinez Ibañez
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Tommaso A
authors.initials: TA
authors.lastname: Dragani
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Manenti
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
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