Expression quantitative trait analysis reveals fine germline transcript regulation in mouse lung tumors

Area of Science:

• Genomics
• Cancer Biology
• Molecular Genetics

Background:

• Gene expression is critical for cellular functions in health and disease.
• Lung tumor multiplicity in mice is genetically linked to the Pulmonary adenoma susceptibility 1 (Pas1) locus.

Purpose of the Study:

• To investigate the genetic control of gene expression in urethane-induced mouse lung tumors.
• To identify genes regulated by the Pas1 locus and associated with lung tumor multiplicity.

Main Methods:

• Genetic linkage analysis of the lung tumor transcriptome in an (A/J x C57BL/6)F4 intercross population.
• Expression quantitative trait locus (eQTL) analysis to identify cis- and trans-acting regulators.
• Association analysis of gene transcript levels with lung tumor multiplicity (Nlung).
• Pathway analysis of identified gene sets.

Main Results:

• Expression levels of 1179 and 1579 genes were modulated by cis- and trans-acting eQTLs, respectively.
• The Pas1 locus region regulated 14 genes in cis and 857 genes in trans.
• Transcript levels of 1124 genes associated with Nlung; 401 of these were regulated by the Pas1 locus genotype.
• Pathway analysis highlighted 14 genes involved in Ras-Erk and Pi3k-Akt signaling.

Conclusions:

• The Pas1 locus is a major regulator of transcription in lung tumor nodules.
• Germline genotype at Pas1 influences gene expression and lung tumor development.
• The Kras gene is a strong candidate effector for the Pas1 locus's role in lung cancer.