Nature Genetics 38, 926 - 930 (2006)
Published online: 2 July 2006; | doi:10.1038/ng1836
A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 miceMinh D To1, Jesus Perez-Losada1, Jian-Hua Mao1, Jeff Hsu1, 3, Tyler Jacks2 & Allan Balmain11
University of California San Francisco (UCSF) Comprehensive Cancer Center, San Francisco, California 94115, USA. 2
Department of Biology, Massachusetts Institute of Technology, and Howard Hughes Medical Institute, Center for Cancer Research, Cambridge, Massachusetts 02139, USA. 3
Present address: Xoma Corp., Berkeley, California 94710, USA.
Correspondence should be addressed to Allan Balmain abalmain@cc.ucsf.edu 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 tumors2,
3 and is a candidate Pas1 gene4. M. spretus mice (SPRET/Ei) carry a Pas1 resistance haplotype for chemically induced lung tumors5. 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.
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