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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)48-55
Number of pages8
JournalNature genetics
Volume37
Issue number1
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Sweet-Cordero, A., Mukherjee, S., Subramanian, A., You, H., Roix, J. J., Ladd-Acosta, C., Mesirov, J., Golub, T. R., & Jacks, T. (2005). An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nature genetics, 37(1), 48-55. https://doi.org/10.1038/ng1490