Microsatellite stable colorectal cancers stratified by the BRAF V600E mutation show distinct patterns of chromosomal instability

Bond, Catherine E., Nancarrow, Derek J., Wockner, Leesa F., Wallace, Leanne, Montgomery, Grant W., Leggett, Barbara A. and Whitehall, Vicki L. J. (2014) Microsatellite stable colorectal cancers stratified by the BRAF V600E mutation show distinct patterns of chromosomal instability. Plos One, 9 3: . doi:10.1371/journal.pone.0091739


Author Bond, Catherine E.
Nancarrow, Derek J.
Wockner, Leesa F.
Wallace, Leanne
Montgomery, Grant W.
Leggett, Barbara A.
Whitehall, Vicki L. J.
Title Microsatellite stable colorectal cancers stratified by the BRAF V600E mutation show distinct patterns of chromosomal instability
Formatted title
Microsatellite stable colorectal cancers stratified by the BRAF V600E mutation show distinct patterns of chromosomal instability
Journal name Plos One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2014-03
Year available 2014
Sub-type Article (original research)
DOI 10.1371/journal.pone.0091739
Open Access Status DOI
Volume 9
Issue 3
Total pages 12
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2015
Language eng
Formatted 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.


Keyword Island methylator phenotype
Comparative genomic hybridization
Copy number alterations
Human colon
Prognosis
Tumorigenesis
Aberrations
Aneuploidy
Heterozygosity
Association
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article ID: e91739

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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