Gene expression phenotypic models that predict the activity of oncogenic pathways

Abstract

High-density DNA microarrays measure expression of large numbers of genes in one assay. The ability to find underlying structure in complex gene expression data sets and rigorously test association of that structure with biological conditions is essential to developing multi-faceted views of the gene activity that defines cellular phenotype. We sought to connect features of gene expression data with biological hypotheses by integrating 'metagene' patterns from DNA microarray experiments in the characterization and prediction of oncogenic phenotypes. We applied these techniques to the analysis of regulatory pathways controlled by the genes HRAS (Harvey rat sarcoma viral oncogene homolog), MYC (myelocytomatosis viral oncogene homolog) and E2F1, E2F2 and E2F3 (encoding E2F transcription factors 1, 2 and 3, respectively). The phenotypic models accurately predict the activity of these pathways in the context of normal cell proliferation. Moreover, the metagene models trained with gene expression patterns evoked by ectopic production of Myc or Ras proteins in primary tissue culture cells properly predict the activity of in vivo tumor models that result from deregulation of the MYC or HRAS pathways. We conclude that these gene expression phenotypes have the potential to characterize the complex genetic alterations that typify the neoplastic state, whether in vitro or in vivo, in a way that truly reflects the complexity of the regulatory pathways that are affected.

The cell cycle and cancer

“…This is driving the concept that, rather than describing cancers according to their site of origin and clinicopathological parameters, tumours might alternatively be classified in terms of the main pathways that drive tumour cell proliferation (eg PI3K-PTEN-mTOR-driven cancer, Wnt-driven cancer, etc.) [122][123][124]. However, molecular tools to measure activation of the signalling pathways in tumour [129].…”

Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective

“…101 Upregulation of certain genes combined with downregulation of other sets of genes has been reported to be characteristic for activation of specific oncogenic pathways. 147 The PI3Kinase signalling pathway is one such major pathway found to be upregulated in cancer in general, and in aggressive subtypes in particular. 109,110 Activation of this pathway may affect sets of genes (expression signature) that may be more robust in determining the involvement of the signalling pathway compared to the regulation of a single gene.…”

Myc pathways provoking cell suicide and cancer

“…Myc target genes have been identified by a number of approaches, most recently in SAGE and microarray screens designed to capture those targets induced or repressed following conditional activation of the oncoprotein (Coller et al, 2000;Boon et al, 2001;Neiman et al, 2001;Schuldiner and Benvenisty, 2001;Godfried et al, 2002;Iritani et al, 2002;Menssen and Hermeking, 2002;Watson et al, 2002;Yu et al, 2002;Ellwood-Yen et al, 2003;Huang et al, 2003). The cast of targets is ponderous (with at least 647 targets already identified, see http://www.myc-cancer-gene.org).…”