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

Abstract

Oncogenes and/or the loss of tumour suppressor genes generally cooperate with each other in transforming cells into cancer cells. A new study identifies a list of genes synergistically regulated by the Ras oncogene and loss of the p53 tumour suppressor gene. Many of these genes are essential for tumour formation in vivo, whereas few of the genes regulated by either Ras or p53 alone are important. This establishes a new approach to finding genes important in tumorigenesis that may also represent novel targets for tumour therapy. A new study identifies a list of genes synergistically regulated by the Ras oncogene and loss of the p53 tumour suppressor gene. A high proportion of these genes are essential for tumour formation in vivo, whereas only very few of the genes regulated by only either Ras or p53 are important. This establishes a new approach to finding genes important in tumourigenesis that may also represent novel targets for tumour therapy. 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.