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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 ( BRAF mut/MSS) cancers (n = 33) and  BRAF  mutant/MSI ( BRAF mut/MSI) cancers (n = 30) were compared for presence of copy number aberrations (CNAs) indicative of CIN, with  BRAF  wild type/MSS ( BRAF wt/MSS) cancers (n = 18) using Illumina CytoSNP-12 arrays.  BRAF mut/MSS and  BRAF wt/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  BRAF mut/MSS cancers having significantly greater proportions of focal CNAs compared to  BRAF wt/MSS cancers (p<0.0001); whereas whole chromosomal arm CNAs were more common in  BRAF wt/MSS cancers (p<0.0001). This related to a reduced average CNA length in  BRAF mut/MSS compared to  BRAF wt/MSS cancers (20.7 Mb vs 33.4 Mb;p<0.0001); and a smaller average percent of CIN affected genomes in  BRAF mut/MSS compared to  BRAF wt/MSS cancers (23.9% vs 34.9% respectively).  BRAF mut/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).  BRAF mut/MSS cancers had more frequent deletion CNAs compared to  BRAF wt/MSS cancers on 6p and 17q at loci not typically correlated with colorectal cancer, and greater amplification CNAs on 8q and 18q compared to  BRAF wt/MSS cancers. These results indicate that comparable rates of CIN occur between MSS subgroups, however significant differences in their patterns of instability exist, with  BRAF mut/MSS cancers showing a ‘focal pattern’ and  BRAF wt/MSS cancers having a ‘whole arm pattern’ of CIN. This and the genomic loci more frequently affected in  BRAF mut/MSS cancers provides further evidence of the biological distinctions of this important cancer subgroup.

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