Oncogenic pathway signatures in human cancers as a guide to targeted therapies

Abstract

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

LAMC2 enhances the metastatic potential of lung adenocarcinoma

“…To evaluate the relationship between LAMC2 mRNA expression level and prognosis in NSCLC, we used three publicly available mRNA microarray data: the first cohort of 204 ADCs from Japanese National Cancer Center (JNCC set; HG-U133A Plus 2.0; GSE31210), 46 the second cohort of a mix of 63 ADCs and 75 SCCs from the Samsung Medical Center (SMC set; HG-U133A Plus 2.0; GSE8894), 47 and the third cohort of 59 ADCs and 52 SCCs from Duke University Medical Center (DUMC set; HG-U133A Plus 2.0; GSE3141). 48 Detailed methods were described in the Supplementary section. IHC in human NSCLC specimens.…”

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].…”

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

“…When E2F3a was ectopically expressed in quiescent mouse fibroblasts (Black et al, 2005), only four of the genes found to be differentially expressed (PCNA, PTMA, MAD2L1 and Rrm2) were common to our lists. When E2F3a was overexpressed in primary mammary epithelial cells (Bild et al, 2006), only PCNA was common to our lists. These differences might reflect the different approaches used in these studies and that key genes controlled by E2F3 may depend on its cellular context.…”