How the BRAF V600E Mutation Defines a Distinct Subgroup of Colorectal Cancer: Molecular and Clinical Implications

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.

Figure 1

Diagram of the mitogen-activated protein kinase pathway. A signalling epidermal growth factor binds to the receptor (EGFR) on the cell surface causing its phosphorylation and activation. The activated signal is passed to scaffolding proteins (GRB2 and SOS) which in turn promotes the removal of GDP from membrane-bound KRAS. KRAS then binds GTP, allowing its activation, and undergoes conformational change to bind and phosphorylate BRAF. The signalling cascade continues through MEK and ERK. Activated ERK translocates to the nucleus where it recruits transcription factors involved in cellular survival and growth. The V600E BRAF mutation allows for constitutive activation of BRAF and continuation of downstream signalling regardless of upstream regulation.

Figure 2

Diagram of the serrated and conventional pathways of colorectal cancer. Bold text indicates the pathways leading to BRAF mutant cancers. ACF: aberrant crypt foci; GCHP: goblet cell hyperplastic polyp; MVHP: microvesicular hyperplastic polyp; SSA: sessile serrated adenoma; TSA: traditional serrated adenoma; TA: tubular adenoma; TVA: tubulovillous adenoma.