A Functional Switch from Lung Cancer Resistance to Susceptibility at the Pas1 Locus in Kras2LA2 Mice

Overview

Journal Nat Genet

Specialty Genetics

Date 2006 Jul 11

PMID 16823377

Citations 32

Authors

Minh D To

Jesus Perez-Losada

Jian-Hua Mao

Jeff Hsu

Tyler Jacks

Allan Balmain

Affiliations

Soon will be listed here.

Abstract

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.

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