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Fine Mapping and Candidate Gene Analyses of Pulmonary Adenoma Resistance 1, a Major Genetic Determinant of Mouse Lung Adenoma Resistance

Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri

Requests for reprints: Ming You, Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Box 8109, 660 Euclid Avenue, St. Louis, MO 63110. Phone: 314-362-9294; Fax: 314-362-9366; E-mail: youm{at}msnotes.wustl.edu.

Pulmonary adenoma resistance 1 (Par1) is a major genetic determinant of mouse lung adenoma resistance. Although Par1 was previously mapped to mouse chromosome 11 by conventional linkage analyses, its candidate region was broad and undefined. In our present study, we generated Par1 congenic mice using two mouse strains A/J (Par1/–) and Mus spretus (Par1/+). Analyzing these congenic mice enabled us to fine map the Par1 quantitative trait loci (QTL) into a 2.0-cM (2.2 Mb) chromosomal region between genetic marker D11Mit70 and the gene Hoxb9. We then conducted systematic candidate gene screening through nucleotide polymorphism and expression analyses. Genes showing differential lung tissue expression or carrying nonsynonymous single nucleotide polymorphisms were identified and discussed. In particular, we evaluated tumor suppressor gene Tob1 for its Par1 candidacy. Our findings have narrowed the Par1 QTL region and will greatly facilitate the identification of the major genetic determinant of mouse lung adenoma resistance. [Cancer Res 2007;67(6):2508–16]