An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis

No citation available. Published: 2004.12.18

Alejandro Sweet-Cordero, Sayan Mukherjee, Aravind Subramanian, Han You, Jeffrey J Roix, Christine Ladd-Acosta, Jill Mesirov, Todd R Golub, & Tyler Jacks

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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.

Keywords: mouse model, kras, GSEA, mantel test, cross-species, lung adenocarcinoma

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Supplemental Data

Description Link/Filename
All datasets in a single zipped file DATASETS.RAR
Original article in Nature Genetics January 2005 http://www.nature.com/cgi-taf/DynaPage.taf?file=/ng/journal/v37/n1/abs/ng1490.html
All figures and tables in a single zipped file figuresandtables.rar
News and views in Nature Genetics http://www.nature.com/cgi-taf/DynaPage.taf?file=/ng/journal/v37/n1/full/ng0105-7.html
Supplementary info on the Nature Genetics web site http://www.nature.com/ng/journal/v37/n1/suppinfo/ng1490_S1.html
All gene sets in a single zipped file GENESETS.RAR
Research highlights in Nature Cancer Reviews http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrc/journal/v5/n1/full/nrc1540_fs.html
Supplementary methods and description (ms doc) 4679_3_supp_0_1100271809.doc
Faculty of 1000 review http://www.f1000biology.com/article/15608639/evaluation