title: Haplotype sharing suggests that a genomic segment containing six genes accounts for the pulmonary adenoma susceptibility 1 (Pas1) locus activity in mice.
abstract: The pulmonary adenoma susceptibility 1 (Pas1) locus affects inherited predisposition and resistance to chemically induced lung tumorigenesis in mice. The A/J and C57BL/6J mouse strains carry the susceptibility and resistance allele, respectively. We identified and genotyped 65 polymorphisms in the Pas1 locus region in 29 mouse inbred strains, and delimited the Pas1 locus to a minimal region of 468 kb containing six genes. That region defined a core Pas1 haplotype with 42 tightly linked markers, including intragenic polymorphisms in five genes (Bcat1, Lrmp, Las1, Ghiso, and Kras2) and amino-acid changes in three genes (Lrmp, Las1, Lmna-rs1). In (A/J x C57BL/6J)F1 mouse lung tumors, the Lmna-rs1 gene was completely downregulated, whereas allele-specific downregulation of the C57BL/6J-derived allele was observed at the Las1 gene, suggesting the potential role of these genes in tumor suppression. These results indicate a complex multigenic nature of the Pas1 locus, and point to a functional role for both intronic and exonic polymorphisms of the six genes of the Pas1 haplotype in lung tumor susceptibility.
authors.affiliation: Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Manenti
authors.forename: Federica
authors.initials: F
authors.lastname: Galbiati
authors.forename: Roberto
authors.initials: R
authors.lastname: Giannì-Barrera
authors.forename: Angela
authors.initials: A
authors.lastname: Pettinicchio
authors.forename: Abraham
authors.initials: A
authors.lastname: Acevedo
authors.forename: Tommaso A
authors.initials: TA
authors.lastname: Dragani
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D000637:Transaminases / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology; D014520:Urethane / Q000633:toxicity
chemical_list: C487460:Las1 protein, mouse; C487461:Lmna-rs1 protein, mouse; C101764:Lrmp protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; D014520:Urethane; C094227:Bcat1 protein, mouse; D000637:Transaminases