Microsatellite Stable Colorectal Cancers Stratified by the BRAF V600E Mutation Show Distinct Patterns of Chromosomal Instability

Abstract

The BRAF (V600E) mutation in colorectal cancers that are microsatellite stable (MSS) confers a poor patient prognosis, whereas BRAF mutant microsatellite-unstable (MSI) colorectal cancers have an excellent prognosis. BRAF wild type cancers are typically MSS and display chromosomal instability (CIN). CIN has not been extensively studied on a genome-wide basis in relation to BRAF mutational status in colorectal cancer. BRAF mutant/MSS (BRAFmut/MSS) cancers (n = 33) and BRAF mutant/MSI (BRAFmut/MSI) cancers (n = 30) were compared for presence of copy number aberrations (CNAs) indicative of CIN, with BRAF wild type/MSS (BRAFwt/MSS) cancers (n = 18) using Illumina CytoSNP-12 arrays. BRAFmut/MSS and BRAFwt/MSS cancers showed comparable numbers of CNAs/cancer at 32.8 and 29.8 respectively. However, there were differences in patterns of CNA length between MSS cohorts, with BRAFmut/MSS cancers having significantly greater proportions of focal CNAs compared to BRAFwt/MSS cancers (p<0.0001); whereas whole chromosomal arm CNAs were more common in BRAFwt/MSS cancers (p<0.0001). This related to a reduced average CNA length in BRAFmut/MSS compared to BRAFwt/MSS cancers (20.7 Mb vs 33.4 Mb;p<0.0001); and a smaller average percent of CIN affected genomes in BRAFmut/MSS compared to BRAFwt/MSS cancers (23.9% vs 34.9% respectively). BRAFmut/MSI cancers were confirmed to have low CNA rates (5.4/cancer) and minimal CIN-affected genomes (average of 4.5%) compared to MSS cohorts (p<0.0001). BRAFmut/MSS cancers had more frequent deletion CNAs compared to BRAFwt/MSS cancers on 6p and 17q at loci not typically correlated with colorectal cancer, and greater amplification CNAs on 8q and 18q compared to BRAFwt/MSS cancers. These results indicate that comparable rates of CIN occur between MSS subgroups, however significant differences in their patterns of instability exist, with BRAFmut/MSS cancers showing a ‘focal pattern’ and BRAFwt/MSS cancers having a ‘whole arm pattern’ of CIN. This and the genomic loci more frequently affected in BRAFmut/MSS cancers provides further evidence of the biological distinctions of this important cancer subgroup.

RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis

“…BRAF mutant/MSI cancers had a low rate of deletion (4/30, 13.3%), which was expected since MSI cancers are known to be diploid [22]. …”

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

“…The somatic inactivation of MMR genes is strongly associated with V600E BRAF mutation (60%), which is virtually absent in Lynch syndrome [80,81]. Hence, somatic BRAF mutation testing has been included into the Lynch syndrome screening algorithm [76,[82][83][84][85][86]. The prognostic and predictive value of coexisting BRAF mutation and MSI is still matter of debate.…”

Differentiation of stem cells derived from carious teeth into dopaminergic‐like cells

“…As such, it is believed that the expression of pro-inflammatory mediators such as IL-1b, IL-2 and TNF-a regulate neurogenesis in an inversely proportional manner (Butovsky et al 2006, Whitney et al 2009 whereby their presence would downregulate the expression of transcription factors such as NEUROG, FLNA and MEF2C. It was further described that the inhibition of neurogenesis was initiated via a de-activation of the WNT pathway (Robel et al 2011, Lian et al 2012, Bond et al 2014). This pathway is well known for promoting the self-renewal of neural progenitors, a reduction in their stemness and a consequent differentiation in a stage-specific manner (Varela-Nallar & Inestrosa 2013).…”