BioProject

To detect genetic variations affecting gene expression in mouse lung tumor tissue, 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 (containing the Kras-37-bp marker) . In particular, susceptible animals carry the A/J-derived version of Pas1 in homozygousity or in heterozygousity, while tumor-resistant animals carry the C57BL/6-derived version. We found that expression levels of 1,179 and 1,579 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 1,124 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. In conclusion, 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. Overall design: Female animals of the lung tumor-susceptible A/J strain (A) were mated with males of the lung tumor-resistant C57BL/6 strain (B), and offspring were bred to the fourth generation (ABF4). At 4 weeks of age, 143 male ABF4 mice were treated with a single intraperitoneal injection of the chemical carcinogen urethane to induce the development of lung tumors. When the animals were 40 weeks of age, they were killed, the lungs were removed for tumor counting (values of lung tumor multiplicity [Nlung] varied substantially among individuals, ranging from 1 to 33 in the animals that developed tumors), and a single lung tumor, 1–1.5 mm in diameter, was excised from each for RNA extraction.