TY - JOUR
T1 - An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis
AU - Sweet-Cordero, Alejandro
AU - Mukherjee, Sayan
AU - Subramanian, Aravind
AU - You, Han
AU - Roix, Jeffrey J.
AU - Ladd-Acosta, Christine
AU - Mesirov, Jill
AU - Golub, Todd R.
AU - Jacks, Tyler
N1 - Funding Information:
We thank P. Tamayo and K. Haigis for comments and critical review of the manuscript and M. You for providing access to the gene expression data and histology slides for the NNK mouse models. This work was supported in part by the National Institutes of Health and the National Cancer Institute. T.J. and T.R.G. are investigators of the Howard Hughes Medical Institute. A.S.-C. was supported in part by grants from the Robert Woods Johnson Foundation (Harold Amos Medical Faculty Development Program) and by a mentored clinical scientist grant from the National Cancer Institute. S.M. received partial support from an Alfred P. Sloan Foundation/U.S. Department of Energy Fellowship in Computational Molecular Biology.
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
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U2 - 10.1038/ng1490
DO - 10.1038/ng1490
M3 - Article
C2 - 15608639
AN - SCOPUS:11244258643
SN - 1061-4036
VL - 37
SP - 48
EP - 55
JO - Nature genetics
JF - Nature genetics
IS - 1
ER -