A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice.
Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1). Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors and is a candidate Pas1 gene. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors. We demonstrate that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events and could have major implications for the design of human association studies to identify cancer susceptibility genes.
To
Minh D
MD
University of California San Francisco (UCSF) Comprehensive Cancer Center, San Francisco, California 94115, USA.
Perez-Losada
Jesus
J
Mao
Jian-Hua
JH
Hsu
Jeff
J
Jacks
Tyler
T
Balmain
Allan
A
D000236:Adenoma / Q000139:chemically induced / Q000235:genetics; D000483:Alleles; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D005260:Female; D020022:Genetic Predisposition to Disease; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D009857:Oncogenes; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012307:Risk Factors; D014520:Urethane / Q000633:toxicity
D002273:Carcinogens; D014520:Urethane; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)