title: Expression quantitative trait analysis reveals fine germline transcript regulation in mouse lung tumors.
abstract: Gene expression modulates cellular functions in both physiologic and pathologic conditions. Herein, we carried out a genetic linkage study on the transcriptome of lung tumors induced by urethane in an (A/J x C57BL/6)F4 intercross population, whose individual lung tumor multiplicity (Nlung) is linked to the genotype at the Pulmonary adenoma susceptibility 1 (Pas1) locus. We found that expression levels of 1179 and 1579 genes are modulated by an expression quantitative trait locus (eQTL) in cis and in trans, respectively (LOD score > 5). Of note, the genomic area surrounding and including the Pas1 locus regulated 14 genes in cis and 857 genes in trans. In lung tumors of the same (A/J x C57BL/6)F4 mice, we found 1124 genes whose transcript levels associated with Nlung (FDR < 0.001). The expression levels of about a third of these genes (n = 401) were regulated by the genotype at the Pas1 locus. Pathway analysis of the sets of genes associated with Nlung and regulated by Pas1 revealed a set of 14 recurrently represented genes that are components or targets of the Ras-Erk and Pi3k-Akt signaling pathways. Altogether our results illustrate the architecture of germline control of gene expression in mouse lung cancer: they highlight the importance of Pas1 as a tumor-modifier locus, attribute to it a novel role as a major regulator of transcription in lung tumor nodules and strengthen the candidacy of the Kras gene as the effector of this locus.
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Chiara E
authors.initials: CE
authors.lastname: Cotroneo
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: Angela
authors.initials: A
authors.lastname: Pettinicchio
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecis
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Dugo
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: tommaso.dragani@istitutotumori.mi.it.
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: D000483:Alleles; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005854:Germ Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics*; D059467:Transcriptome
chemical_list: D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras); C495971:Hras protein, mouse
keywords: Animal models; Expression quantitative trait loci; Gene expression; Lung cancer; Pas1; Transcriptome