Abstract
The BRAF oncogene is an integral component of the MAP kinase pathway, and an activating V600E mutation occurs in 15% of sporadic colorectal cancer. This is an early event in serrated pathway tumourigenesis, and the BRAF V600E has been commonly associated with the CpG island methylator phenotype, microsatellite instability (MSI), and a consistent clinical presentation including a proximal location and predilection for elderly females. A proportion of the BRAF mutant lesions remain as microsatellite stable (MSS), and in contrast to the MSI cancers, they have an aggressive phenotype and correlate with poor patient outcomes. Recent studies have found that they have clinical and molecular features of both the BRAF mutant/MSI and the conventional BRAF wild-type cancers and comprise a distinct colorectal cancer subgroup. This review highlights the importance of the BRAF mutation occurring in colorectal cancer stratified for molecular background and discusses its prognostic and clinical significance.
Highlights
In colorectal cancer, the presence of a BRAF mutation can be associated with an aggressive phenotype and is a key prognostic biomarker for poor outcome in latestage disease
The class of BRAF mutation has clinical implications regarding the type of BRAF inhibitor prescribed as it has been found that FDA-approved BRAF inhibitors vemurafenib and dabrafenib are only effective against class 1 monomer-type mutations (V600 mutations) and not the class 2 mutations that function as dimers due to an elevated drug affinity for a site within the first dimer which causes an allosteric effect and subsequent reduction of binding to the second dimer [24]
A study that found no significant survival benefit for patients with mutant BRAF treated with cetuximab concluded that the relatively low frequency of the BRAF mutation and its strong correlation with negative patient outcome may be contributing to the lack of significant difference in response to anti-EGFR treatment strategies and that larger patient cohorts are required to assess the predictive significance of mutant BRAF [125, 126]
Summary
The presence of a BRAF mutation can be associated with an aggressive phenotype and is a key prognostic biomarker for poor outcome in latestage disease. The BRAF V600E mutation occurs early in tumourigenesis and is highly correlated with the serrated neoplasia pathway of colorectal cancer This pathway describes progression of a serrated precursor lesion, often followed by the onset of epigenetic instability involving promoter methylation and silencing of key tumour suppressor genes, and accounts for 15%-20% of sporadic colorectal cancer [1, 2]. BRAF mutant/MSS cancers form a distinct colorectal cancer entity that shares clinical and molecular features with both BRAF mutant/MSI serrated pathway cancers and the BRAF wild-type cancers of the conventional pathway [9,10,11] This latter pathway involves the previously well-defined series of genetic aberrations such as APC.
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