A Molecular Signature for Oncogenic BRAF in Human Colon Cancer Cells is Revealed by Microarray Analysis

T.      Joyce; E.      Oikonomou; V.      Kosmidou; E.      Makrodouli; I.      Bantounas; S.      Avlonitis; G.      Zografos; A.      Pintzas

Abstract

Sporadic colorectal cancer develops through a number of functional mutations. Key events are mutually exclusive mutations in BRAF or RAS oncogenes. Signatures for BRAF oncogene have been revealed in melanoma. In a previous study we have reported a molecular signature for HRAS and KRAS mutations in colorectal cell lines that also showed an EMT phenotype for HRAS.

In this study we report a molecular profile for a BRAF oncogenic mutation BRAFV600E in colon using the Illumina 45,000 gene microarray. Key differentially expressed genes have been identified from the array analysis further verified by qPCR analysis.

Ingenuity pathway analysis such as microsatellite instability, kinase signalling, apoptosis, WNT and Integrin signalling is presented. MutBRAF transforms cells through cross talk with developmental pathways Hedgehog and Wnt, as well as by deregulation of colorectal cancer related kinase pathways, like PI3K.

Differential gene expression of BRAFV600E in colon as compared to those associated with RAS oncogenes is presented, as well as similarities and differences between oncogenic BRAF signatures in colon as compared to thyroid and melanoma are highlighted. Novel selected genes/pathways are validated in cell lines and clinical samples bearing BRAFV600E and may serve as markers/targets for personalised diagnosis/therapy/resistance of colorectal cancer.

Keywords: BRAF, colorectal cancer, gene expression profile, oncogenes, signalling pathways, signatures, chromosomal instability, myotonic dystrophy protein kinase, Epithelial-Mesenchymal Transition, extracellular signal-related kinase, Host Cell Factor 1, microsatellite instability, proliferator-activated receptor, vascular endothelial growth factor.