Cancer Program Publication

An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis
ProjectCancer Susceptibility
Additional Projects/
Categories		 Lung Cancer
Abstract 
Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Here we describe a method for comparing mouse models of cancer with human tumors using gene-expression profiling. We applied this method to the analysis of a model of Kras2-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model. Furthermore, we found that whereas a gene-expression signature of KRAS2 activation was not identifiable when analyzing human tumors with known KRAS2 mutation status alone, integrating mouse and human data uncovered a gene-expression signature of KRAS2 mutation in human lung cancer. We confirmed the importance of this signature by gene-expression analysis of short hairpin RNA−mediated inhibition of oncogenic Kras2. These experiments identified both a pattern of gene expression indicative of KRAS2 mutation and potential effectors of oncogenic KRAS2 activity in human cancer. This approach provides a strategy for using genomic analysis of animal models to probe human disease.
AuthorsAlejandro Sweet-Cordero, Sayan Mukherjee, Aravind Subramanian, Han You, Jeffrey J Roix, Christine Ladd-Acosta, Jill Mesirov, Todd R Golub, & Tyler Jacks
Publication Date12/19/2004
Contact emails tjacks@mit.edu
golub@broad.mit.edu
Publication URLhttp://www.nature.com/cgi-taf/DynaPage.taf?file=/ng/journal/vaop/ncurrent/full/ng1490.html
Keywordsmouse model, kras, GSEA, mantel test, cross-species, lung adenocarcinoma
 
Supplemental Information
URLs
NameURL
Original article in Nature Genetics January 2005http://www.nature.com/cgi-taf/DynaPage.taf?file=/ng/journal/v37/n1/abs/ng1490.html
News and views in Nature Geneticshttp://www.nature.com/cgi-taf/DynaPage.taf?file=/ng/journal/v37/n1/full/ng0105-7.html
Supplementary info on the Nature Genetics web sitehttp://www.nature.com/ng/journal/v37/n1/suppinfo/ng1490_S1.html
Research highlights in Nature Cancer Reviewshttp://www.nature.com/cgi-taf/DynaPage.taf?file=/nrc/journal/v5/n1/full/nrc1540_fs.html
Faculty of 1000 reviewhttp://www.f1000biology.com/article/15608639/evaluation
Files
DescriptionFile
All datasets in a single zipped fileDATASETS.RAR
All figures and tables in a single zipped filefiguresandtables.rar
All gene sets in a single zipped fileGENESETS.RAR
Supplementary methods and description (ms doc)4679_3_supp_0_1100271809.doc