Complex genetic control of lung tumorigenesis in resistant mice strains

Alice Dassano, Giulia Pintarelli, Chiara E. Cotroneo, Angela Pettinicchio, Elena Forcati, Loris De Cecco, Andrea Borrego, Francesca Colombo, Tommaso A. Dragani, Giacomo Manenti

Research output: Contribution to journalArticlepeer-review

Abstract

The SM/J mouse strain is resistant to chemically-induced lung tumorigenesis despite having a haplotype, in the pulmonary adenoma susceptibility locus (Pas1) locus, that confers tumor susceptibility in other strains. To clarify this inconsistent genotype-phenotype correlation, we crossed SM/J mice with another resistant strain and conducted genome-wide linkage analysis in the (C57BL/6J × SM/J)F2 progeny exposed to urethane to induce lung tumors. Overall, >80% of F2 mice of both sexes developed from 1 to 20 lung tumors. Genotyping of 372 F2 mice for 744 informative non-redundant SNPs dispersed over all autosomal chromosomes revealed four quantitative trait loci (QTLs) affecting lung tumor multiplicity, on chromosomes 3 (near rs13477379), 15 (rs6285067), 17 (rs33373629) and 18 (rs3706601), all with logarithm of the odds (LOD) scores >5. Four QTLs modulated total lung tumor volume, on chromosome 3 (rs13477379), 10 (rs13480702), 15 (rs6285067) and 17 (rs3682923), all with LOD scores >4. No QTL modulating lung tumor multiplicity or total volume was detected in Pas1 on chromosome 6. The present study demonstrates that the SM/J strain carries, at the Pas1 locus, the resistance allele: a finding that will facilitate identification of the Pas1 causal element. More generally, it demonstrates that lung tumorigenesis is under complex polygenic control even in a pedigree with low susceptibility to this neoplasia, suggesting that the genetics of lung tumorigenesis is much more complex than evidenced by the pulmonary adenoma susceptibility and resistance loci that have, so far, been mapped in a small number of crosses between a few inbred strains.

Original languageEnglish
Pages (from-to)2281-2286
Number of pages6
JournalCancer Science
Volume108
Issue number11
DOIs
Publication statusPublished - Nov 1 2017

Keywords

  • Genetic linkage
  • genetic loci
  • lung cancer
  • Pas1
  • quantitative trait loci

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Complex genetic control of lung tumorigenesis in resistant mice strains'. Together they form a unique fingerprint.

Cite this