Mouse pulmonary adenoma susceptibility 1 locus is an expression QTL modulating Kras-4A.

Alice Dassano,Elisa Frullanti,Giacomo Manenti,Angela Pettinicchio,Loris De Cecco,Francesca Colombo,Andrea Borrego,Olga Célia Martinez Ibañez,Antonella Galvan,Tommaso A Dragani,Gaia Trincucci,Kent W Hunter

doi:10.1371/journal.pgen.1004307

Alice Dassano, Elisa Frullanti + Show 10 more

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https://doi.org/10.1371/journal.pgen.1004307

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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.

Highlights

The Pulmonary adenoma susceptibility 1 (Pas1) locus, mapping in the distal region of chromosome 6, is the major modulator of lung tumor susceptibility in mice [1,2]
In mouse models in which mutant Kirsten rat sarcoma viral oncogene homolog (Kras) can be activated by somatic recombination in the lung, animals are highly susceptible to lung tumorigenesis and develop multiple lung tumors at 100% incidence with a short latency [10,11]
The study found that mice susceptible to lung tumors have relatively more Kras4A messenger RNA than resistant mice and that this difference may be due to small variations in the DNA near or within this gene

Summary

Introduction

The Pulmonary adenoma susceptibility 1 (Pas1) locus, mapping in the distal region of chromosome 6, is the major modulator of lung tumor susceptibility in mice [1,2]. These genes are branched chain aminotransferase 1 (Bcat1), lymphoidrestricted membrane protein (Lrmp), cancer susceptibility candidate 1 (Casc1), LYR motif containing 5 (Lyrm5), v-Ki-ras Kirsten rat sarcoma viral oncogene homolog (Kras) and intermediate filament tail domain containing 1 (Ifltd1) Four of these genes, namely Lrmp, Casc, Kras and Ifltd, have been singled out as candidate genes for Pas locus functions in fine-mapping studies [4,5,6]. Given the frequent occurrence of activating Kras mutations in mouse lung tumors, an increase in Kras gene expression in lung tumor tissue could be expected to raise the level of active Kras protein, thereby providing the growth advantage characteristic of neoplasms Evidence supporting this mechanism was provided by the observation that, in mice, Kras mRNA levels in normal lung tissue were ,2-fold higher in strains susceptible to lung tumorigenesis (both highly susceptible A/J mice and intermediate-susceptible FVB/N and 129/Sv mice) than in a resistant strain (C57BL/6) [13]

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