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Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype

Abstract

Understanding the molecular underpinnings of cancer is of critical importance to the development of targeted intervention strategies. Identification of such targets, however, is notoriously difficult and unpredictable. Malignant cell transformation requires the cooperation of a few oncogenic mutations that cause substantial reorganization of many cell features1 and induce complex changes in gene expression patterns2,3,4,5,6. Genes critical to this multifaceted cellular phenotype have therefore only been identified after signalling pathway analysis7,8,9,10 or on an ad hoc basis4,11,12,13,14. Our observations that cell transformation by cooperating oncogenic lesions depends on synergistic modulation of downstream signalling circuitry15,16,17 suggest that malignant transformation is a highly cooperative process, involving synergy at multiple levels of regulation, including gene expression. Here we show that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state of murine and human colon cells. Notably, 14 out of 24 ‘cooperation response genes’ were found to contribute to tumour formation in gene perturbation experiments. In contrast, only 1 in 14 perturbations of the genes responding in a non-synergistic manner had a similar effect. Synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy, and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain- and loss-of-function mutations.

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Figure 1: Identification and characterization of cooperation response genes (CRGs).
Figure 2: Differential expression and synergy scores of CRGs in mp53/Ras cells and CRG co-regulation in human colon cancer.
Figure 3: Synergistic response of downstream genes to oncogenic mutations is a strong predictor for critical role in malignant transformation.
Figure 4: CRG perturbations reduce tumour formation of both mp53/Ras and human cancer cells.

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Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited in the NCBI GEO database under accession number GSE9199.

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Acknowledgements

We thank D. Bohmann, C. Jordan and M. Noble for discussion; C. Brower, A. Cardillo, A. Petenkaya, L. Salamone, A. Brooks, Y. Xiao, S. Welle and A. Rosenberg for assistance with microarray data analysis; A. Burgess, R. Whitehead, J. Filmus and L. Milner for materials; and L. Maquat for sharing equipment. This work was supported in part by NIH grants CA90663, CA120317, GM075299 and a James P. Wilmot Cancer Center pilot grant. H.R.M. was supported in part by NIH T32 CA09363, P.S. by NIH K99 LM009477. This work is dedicated to A. Yakovlev.

Author Contributions H.L. conceived and directed the project. H.R.M., E.R.S., G.C., C.K. and B.S. designed and carried out experiments. S.-R.C and L.N. carried out experiments. P.S. consulted on and performed statistical analysis of microarray and tumour formation data. L.K. and A.Y. designed statistical methods to analyse microarray data. H.R.M. and H.L. wrote the paper.

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Correspondence to Hartmut Land.

Supplementary information

Supplementary Information 1

The file contains Supplementary Figures 1-13 and Legends, Supplementary Tables 1-10, Supplementary Methods and Supplementary References. (PDF 3143 kb)

Supplementary Information 2

This file contains raw and normalized gene expression values from Affymetrix microarrays and associated p values, fold changes and cooperativity scores for the 95 CRGs identified. (XLS 70 kb)

Supplementary Information 3

This file contains normalized gene expression values from TaqMan Low Density arrays (TLDA) and associated fold changes and cooperativity scores for the 95 CRGs identified. (XLS 30 kb)

Supplementary Information 4

This file contains raw and normalized gene expression values from Affymetrix microarrays and associated p values, fold changes and cooperativity scores for the non-CRGs chosen for perturbation experiments. (XLS 22 kb)

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McMurray, H., Sampson, E., Compitello, G. et al. Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype. Nature 453, 1112–1116 (2008). https://doi.org/10.1038/nature06973

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