Genetic linkage analysis identifies Pas1 as the common locus modulating lung tumorigenesis and acute inflammatory response in mice.
Selective breeding for the acute inflammatory response (AIR) generated two mouse lines characterized by maximum (AIRmax) and minimum (AIRmin) responses, explained by the additive effect of alleles differentially fixed in quantitative trait loci (QTLs). These mice also differ in their susceptibility to lung tumorigenesis, raising the possibility that the same loci are involved in the control of both phenotypes. To map the QTLs responsible for the different phenotypes, we carried out a genome-wide linkage analysis using single-nucleotide polymorphism arrays in a pedigree consisting of 802 mice, including 693 (AIRmax × AIRmin)F2 intercross mice treated with urethane and phenotyped for AIR and lung tumor multiplicity. We mapped five loci on chromosomes 4, 6, 7, 11 and 13 linked to AIR (logarithm of odds (LOD)=3.56, 3.52, 15.74, 7.74 and 3.34, respectively) and two loci linked to lung tumor multiplicity, on chromosomes 6 and 18 (LOD=12.18 and 4.69, respectively). The known pulmonary adenoma susceptibility 1 (Pas1) locus on chromosome 6 was the only locus linked to both phenotypes, suggesting that alleles of this locus were differentially fixed during breeding and selection of AIR mice. These results represent a step toward understanding the link between inflammation and cancer.
Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
A
A
Galvan
W
W
Cabrera
F
F
Vorraro
J R
JR
Jensen
A
A
Borrego
N
N
Starobinas
O G
OG
Ribeiro
M
M
De Franco
S
S
Knott
T A
TA
Dragani
G
G
Manenti
O C M
OC
Ibañez
D000483:Alleles; D000818:Animals; D001947:Breeding; D063646:Carcinogenesis / Q000235:genetics*; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics; D008040:Genetic Linkage; D007249:Inflammation / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci