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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.

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Figure 1: Schematic representation of GSEA across species and data sets.
Figure 2: KRAS2 signature in two human data sets.
Figure 3: The KRAS2 signature is enriched in pancreatic adenocarcinoma.
Figure 4: Real-time PCR analysis of expression of selected KRAS2 signature genes.
Figure 5: Knock-down of KRAS2 in the human lung cancer cell line A549.

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Acknowledgements

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.

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Correspondence to Tyler Jacks.

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Supplementary information

Supplementary Fig. 1

Representative example of KrasLA murine lung tumor histology. (PDF 40 kb)

Supplementary Fig. 2

Representative example of Bonner et al carcinogen induced lung tumor histology. (PDF 70 kb)

Supplementary Fig. 3

Distribution of ES scores generated from random gene sets. (PDF 171 kb)

Supplementary Fig. 4

ES scores obtained from gene sets from permuted mouse phenotypes. (PDF 171 kb)

Supplementary Table 1

KrasLA model up-regulated gene set. (XLS 152 kb)

Supplementary Table 2

KrasLA model down-regulated gene set. (XLS 130 kb)

Supplementary Table 3

Venn diagram of KrasLA model and various cancer subtypes. (PDF 51 kb)

Supplementary Table 4

Adenocarcinoma signature. (XLS 42 kb)

Supplementary Table 5

GSEA results for Boston & Ann Arbor lung adenocarcinomas Kras mutant vs. wild-type. (PDF 44 kb)

Supplementary Table 6

Kras signature. (XLS 39 kb)

Supplementary Table 7

GSEA of Kras signature on human datasets. (PDF 46 kb)

Supplementary Table 8

Kras signature in A549 knockdown. (XLS 24 kb)

Supplementary Methods (PDF 4143 kb)

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Sweet-Cordero, A., Mukherjee, S., Subramanian, A. et al. An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nat Genet 37, 48–55 (2005). https://doi.org/10.1038/ng1490

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