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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We thank M. Daly at The Broad Institute of Harvard/Massachusetts General Hospital and MIT, the Wellcome Trust Center for Human Genetics, and Perlegen Sciences for releasing inbred laboratory mouse SNP data. We thank D. Jia and W. Wen for laboratory assistance. We also thank A. Malkinson for providing information on lung tumor multiplicity in mice. This work was supported by grants from the US National Institutes of Health (CA099187, CA099147, ES012063 and ES013340).
Distribution of SNP positions and LD structure across the mouse genome. (PDF 103 kb)
Haplotype-based association analysis of urethane-induced lung adenoma incidence in laboratory inbred mice. (PDF 148 kb)
LD map of the Pas1 locus associated with lung tumor adenoma development. (PDF 135 kb)
Fine-mapping of the CLAS3 genetic locus. (PDF 137 kb)
LD map of the Pas1 locus associated with lung tumor adenoma development. (PDF 1151 kb)
Genomic organization and verification of Casc1 knockout mouse. (PDF 42 kb)
Mouse inbred strains and lung tumor susceptibility. (PDF 65 kb)
Primer sequences. (PDF 75 kb)
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