Abstract 2422: Microsatellite stable colorectal cancers stratified by the BRAF V600E mutation show distinct patterns of chromosomal instability
Authors: Bond Catherine E. , Nancarrow Derek J. , Wockner Leesa F. , Wallace Leanne , Montgomery Grant W. , Leggett Barbara A. , Whitehall Vicki L. 
Published: May 2015

The BRAF (V600E) mutation in colorectal cancers that are microsatellite stable (MSS) confers a very 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 is associated with a poor prognosis but 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 per cancer at 32.8 and 29.8 respectively. However there were distinct differences in patterns of CNA length between MSS cohorts, with BRAFmut/MSS cancers having a significantly greater proportion of focal CNAs compared to BRAFwt/MSS cancers (p&lt;0.0001); whereas whole chromosomal arm CNAs were more common in BRAFwt/MSS cancers (p&lt;0.0001). This related to a reduced average CNA length in BRAFmut/MSS compared to BRAFwt/MSS cancers (20.7Mb vs 33.4Mb; p&lt;0.0001); and a smaller average percentage 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 per cancer) and minimal CIN-affected genomes (average of 4.5%) compared to MSS cohorts (p&lt;0.0001). BRAFmut/MSS cancers had more frequent deletion CNAs compared to BRAFwt/MSS cancers on 17q and 6p at loci not typically correlated with colorectal cancer, and more frequent amplification CNAs on 8q and 18q compared to BRAFwt/MSS cancers.

These results indicate that although comparable rates of CIN occur between MSS subgroups, significant differences in their patterns of instability exist as BRAFmut/MSS cancers display a ‘focal pattern’ and BRAFwt/MSS cancers have more a ‘whole arm pattern' of CIN. This and the genomic loci more frequently affected in BRAFmut/MSS cancers may warrant extended studies to ascertain correlations with clinical data.

Overall this investigation has identified that differing patterns of genomic instability exist between the two MSS colorectal subgroups and provides further evidence of the biological distinctions of the aggressive BRAFmut/MSS cancers.

Citation Format: Catherine E. Bond, Derek J. Nancarrow, Leesa F. Wockner, Leanne Wallace, Grant W. Montgomery, Barbara A. Leggett, Vicki LJ Whitehall. Microsatellite stable colorectal cancers stratified by the BRAF V600E mutation show distinct patterns of chromosomal instability. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2422. doi:10.1158/1538-7445.AM2014-2422