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.
Highlights
The BRAF V600E mutation is present in approximately 10– 15% of sporadic colorectal cancer (CRC) [1] and is a hallmark of the serrated neoplastic pathway of CRC, where cancers develop from serrated precursor polyps [2,3]
The BRAFwt/microsatellite stable (MSS) cohort had a significantly higher propensity for whole chromosome arm copy number aberrations (CNAs) events at 32% compared to the BRAFmut/MSS cohort at 17% (p,0.0001) (Table 2). This corresponded to a significantly higher average rate of whole chromosome arm CNAs per cancer in BRAFwt/MSS compared to BRAFmut/MSS cancers (p = 0.04); and a greater average proportion of genome affected by whole arm events in BRAFwt/MSS compared to BRAFmut/MSS cancers (22% vs 12%, p = 0.02) (Table 2)
This study has shown that BRAFmut/MSS colorectal cancers predominantly harbour focal or targeted CNAs, whereas the BRAFwt/MSS colorectal cancers have significantly more frequent whole chromosome arm CNAs
Summary
The BRAF V600E mutation is present in approximately 10– 15% of sporadic colorectal cancer (CRC) [1] and is a hallmark of the serrated neoplastic pathway of CRC, where cancers develop from serrated precursor polyps [2,3]. The CpG Island Methylator Phenotype (CIMP) is strongly associated with presence of the BRAF mutation [2,4,5]. In approximately half of these BRAF mutant cancers, CIMP related methylation and silencing of the DNA mismatch repair gene, MLH1, results in widespread frameshift mutations known as microsatellite instability (MSI). The remaining BRAF mutant cancers do not methylate MLH1 and are microsatellite stable (MSS). These BRAF mutant/MSS cancers have not been as well studied, but importantly confer a very poor patient prognosis [9,10,11]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call