title: 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.
authors.affiliation: Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Bond
authors.affiliation: Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Oncogenomics Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Nancarrow
authors.affiliation: Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Leesa F
authors.initials: LF
authors.lastname: Wockner
authors.affiliation: Molecular Epidemiology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Leanne
authors.initials: L
authors.lastname: Wallace
authors.affiliation: Molecular Epidemiology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Medicine, University of Queensland, Brisbane, Queensland, Australia; Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leggett
authors.affiliation: Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Pathology Queensland, Brisbane, Queensland, Australia.
authors.forename: Vicki L J
authors.initials: VL
authors.lastname: Whitehall
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf