title: An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis.
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.
authors.affiliation: MIT Center for Cancer Research, Building E17-517, 40 Ames Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sweet-Cordero
authors.forename: Sayan
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.forename: Han
authors.initials: H
authors.lastname: You
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Roix
authors.forename: Christine
authors.initials: C
authors.lastname: Ladd-Acosta
authors.forename: Jill
authors.initials: J
authors.lastname: Mesirov
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D015870:Gene Expression / Q000502:physiology*; D020869:Gene Expression Profiling; D008175:Lung Neoplasms / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins