Nature Genetics 38, 888 - 895 (2006)
Published online: 23 July 2006; | doi:10.1038/ng1849
Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred micePengyuan Liu1, 2, Yian Wang1, 2, Haris Vikis1, 2, Anna Maciag1, 2, Daolong Wang1, Yan Lu1, Yan Liu1 & Ming You11
Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA. 2
These authors contributed equally to this work.
Correspondence should be addressed to Ming You youm@msnotes.wustl.edu We performed a whole-genome association analysis of lung tumor susceptibility using dense SNP maps ( 1 SNP per 20 kb) in inbred mice. We reproduced the pulmonary adenoma susceptibility 1 (Pas1) locus identified in previous linkage studies and further narrowed this quantitative trait locus (QTL) to a region of less than 0.5 Mb in which at least two genes, Kras2 (Kirsten rat sarcoma oncogene 2) and Casc1 (cancer susceptibility candidate 1; also known as Las1), are strong candidates. Casc1 knockout mouse tumor bioassays showed that Casc1-deficient mice were susceptible to chemical induction of lung tumors. We also found three more genetic loci for lung adenoma development. Analysis of one of these candidate loci identified a previously uncharacterized gene Lasc1, bearing a nonsynonymous substitution (D102E). We found that the Lasc1 Glu102 allele preferentially promotes lung tumor cell growth. Our findings demonstrate the prospects for using dense SNP maps in laboratory mice to refine previous QTL regions and identify genetic determinants of complex traits.
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