Role of BRAF-V600E in the serrated pathway of colorectal tumourigenesis

• Published in: The Journal of pathology 2007-06, Vol.212 (2), p.124-133
• Main Authors: Minoo, P, Moyer, MP, Jass, JR
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Apoptosis - genetics; Biological and medical sciences; BRAF-V600E; Cell Line; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; CIMP; Colon - pathology; colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; CpG Islands - genetics; DNA methylation; Epithelial Cells - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Intestinal Mucosa - pathology; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Methylation; Microsatellite Instability; Models, Biological; MSI-H; Mutation; MutL Protein Homolog 1; Neoplasm Invasiveness; Neoplasm Proteins - genetics; Nuclear Proteins - genetics; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins B-raf - genetics; sessile serrated adenoma; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2160

There is increasing evidence for an alternative pathway of sporadic colorectal tumourigenesis that is associated with DNA microsatellite instability (MSI), due to methylation and loss of expression of the mismatch repair gene MLH1. Recent studies have highlighted a serrated pathway of colorectal cancer (CRC) in which serrated polyps with activating mutations in BRAF progress to CRCs with MSI following methylation and silencing of MLH1. The present study provides a novel mechanistic experimental model for these clinical observations. We investigated the role of BRAF activating mutation (BRAF-V600E) in colorectal tumourigenesis by studying the effects of forced expression of BRAF-V600E in the ‘normal' colon epithelial NCM460 cell line and by targeting endogenous BRAF-V600E in MSI-High (MSI-H) colon cancer cell lines. The findings indicate that BRAF mutation in colon epithelial cells contributes to a gain in resistance towards apoptotic stimuli, which is likely to be an important characteristic of pre-malignant serrated lesions. BRAF-V600E also plays a role in the development and maintenance of transformed and invasive phenotypes in colon epithelial cells. Our findings also suggest that BRAF mutation potentiates promoter hypermethylation of the MLH1 gene promoter. Together, these results highlight BRAF as a potential target for therapeutic intervention in sporadic MSI-H colorectal cancers. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.