title: Multigenic nature of the mouse pulmonary adenoma progression 1 locus.
abstract: BACKGROUND
  In an intercross between the SWR/J and BALB/c mouse strains, the pulmonary adenoma progression 1 (Papg1) locus on chromosome 4 modulates lung tumor size, one of several measures of lung tumor progression. This locus has not been fully characterized and defined in its extent and genetic content. Fine mapping of this and other loci affecting lung tumor phenotype is possible using recombinant inbred strains.
  
  
  RESULTS
  A population of 376 mice, obtained by crossing mice of the SWR/J strain with CXBN recombinant inbred mice, was treated with a single dose of urethane and assayed for multiplicity of large lung tumors (N2lung). A genome-wide analysis comparing N2lung with 6364 autosomal SNPs revealed multiple peaks of association. The Papg1 locus had two peaks, at rs3654162 (70.574 Mb, -logP=2.8) and rs6209043 (86.606 Mb, -logP=2.7), joined by an interval of weaker statistical association; these data confirm the presence of Papg1 on chromosome 4 and reduce the mapping region to two stretches of ~6.8 and ~4.2 Mb, in the proximal and distal peaks, respectively. The distal peak included Cdkn2a, a gene already proposed as being involved in Papg1 function. Other loci possibly modulating N2lung were detected on chromosomes 5, 8, 9, 11, 15, and 19, but analysis for linkage disequilibrium of these putative loci with Papg1 locus suggested that only those on chromosomes 11 and 15 were true positives.
  
  
  CONCLUSIONS
  These findings suggest that Papg1 consists, most likely, of two distinct, nearby loci, and point to putative additional loci on chromosomes 11 and 15 modulating lung tumor size. Within Papg1, Cdkn2a appears to be a strong candidate gene while additional Papg1 genes await to be identified. Greater knowledge of the genetic and biochemical mechanisms underlying the germ-line modulation of lung tumor size in mice is relevant to other species, including humans, in that it may help identify new therapeutic targets in the fight against tumor progression.
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Via Amadeo 42, Milan, 20133, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Dassano
authors.forename: Sara
authors.initials: S
authors.lastname: Noci
authors.forename: Federica
authors.initials: F
authors.lastname: Galbiati
authors.forename: Francesca
authors.initials: F
authors.lastname: Colombo
authors.forename: Gaia
authors.initials: G
authors.lastname: Trincucci
authors.forename: Angela
authors.initials: A
authors.lastname: Pettinicchio
authors.forename: Tommaso A
authors.initials: TA
authors.lastname: Dragani
authors.forename: Giacomo
authors.initials: G
authors.lastname: Manenti
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014520:Urethane / Q000633:toxicity
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D014520:Urethane