Multiple oncogenic pathway signatures show coordinate expression patterns in human prostate tumors

Abstract

Background: Gene transcription patterns associated with activation of oncogenes Myc, c-Src, beta-catenin, E2F3, H-Ras, HER2, EGFR, MEK, Raf, MAPK, Akt, and cyclin D1, as well as of the cell cycle and of androgen signaling have been generated in previous studies using experimental models. It was not clear whether genes in these "oncogenic signatures" would show coordinate expression patterns in human prostate tumors, particularly as most of the signatures were derived from cell types other than prostate.

Principal findings: The above oncogenic pathway signatures were examined in four different gene expression profile datasets of human prostate tumors (representing approximately 250 patients in all), using both Q1-Q2 and one-sided Fisher's exact enrichment analysis methods. A significant fraction (approximately 5%) of genes up-regulated experimentally by Myc, c-Src, HER2, Akt, or androgen were co-expressed in human tumors with the oncogene or biomarker corresponding to the pathway signature. Genes down-regulated experimentally, however, did not show anticipated patterns of anti-enrichment in the human tumors.

Conclusions: Significant subsets of the genes in these experimentally-derived oncogenic signatures are relevant to the study of human prostate cancer. Both molecular biologists and clinical researchers could focus attention on the relatively small number of genes identified here as having coordinate patterns that arise from both the experimental system and the human disease system.

Figure 1. Gene expression patterns indicative of oncogenic pathway deregulation.

RNA profiling datasets were collected from various published studies (described in Table 2) in which a particular pathway was activated in an experimental model. Expression patterns are represented as a color map. Each row represents a gene; each column represents a sample. The level of expression of each gene in each sample is represented using a yellow–blue color scale (yellow: high expression). Pathways represented are the following: (A) Myc, c-Src, beta-catenin, E2F3, and H-Ras, from the study by Bild et al. ; (B) erbB-2 (HER2), EGFR, MEK, Raf, and MAPK from Creighton et al. ; (C) the cell cycle from Whitfield et al. ; (D) androgen receptor (AR) signaling, from Deprimo et al. ; (E) AR signaling, from Chen et al. ; (F) Myc, from Coller et al. ; (G) cyclin D1, from Lamb et al. ; (H) Akt, from Majumder et al. . (I) Graphical representation of the significance of gene overlap (by one-sided Fisher's exact test, using as the reference population the entire set of 14130 genes represented among any of the array platforms) between the various pathway signatures (focusing here on the sets of genes up-regulated in each signature).

Figure 2. Patterns of enrichment involving selected oncogenes (KLK3 i.e. PSA, MYC, SRC, ERBB2, EGFR, CCND1 i.e. cyclin D1, and AKT1) and their corresponding pathway signature genes.

(A) Schematic overview of Q1-Q2 enrichment analysis. Enrichment is defined as a significant number of genes in the experimental set being located at or near the top of a population of genes rank-ordered by a given metric applied to the human tumor dataset. (B) Results of enrichment analysis in four different gene expression profile datasets of human prostate tumors –. Patterns of consensus among the various datasets (i.e. patterns observed in at least 2 or 3 datasets) are also represented. For each oncogene-to-pathway association, a red square indicates that genes in the pathway were enriched within the top genes most correlated with the oncogene. Anti-enrichment (blue square) indicates that genes in the pathway overlapped with the genes most anti-correlated with the oncogene. Associations between a given gene and its corresponding oncogenic pathway signature are highlighted with black outline.