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

Catherine E Bond; Derek J Nancarrow; Leesa F Wockner; Leanne Wallace; Grant W Montgomery; Barbara A Leggett; Vicki L J Whitehall

doi:10.1371/journal.pone.0091739

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

PLoS One. 2014 Mar 20;9(3):e91739. doi: 10.1371/journal.pone.0091739. eCollection 2014.

Authors

Catherine E Bond¹, Derek J Nancarrow², Leesa F Wockner³, Leanne Wallace⁴, Grant W Montgomery⁴, Barbara A Leggett⁵, Vicki L J Whitehall⁶

Affiliations

¹ Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
² Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Oncogenomics Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³ Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴ Molecular Epidemiology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵ 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.
⁶ Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Pathology Queensland, Brisbane, Queensland, Australia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Amino Acid Substitution / genetics*
Chromosomal Instability / genetics*
Cohort Studies
Colorectal Neoplasms / genetics*
DNA Copy Number Variations / genetics
Female
Genome, Human / genetics
Humans
Male
Microsatellite Instability*
Mutation / genetics*
Proto-Oncogene Proteins B-raf / genetics*
Sequence Deletion

Substances

BRAF protein, human
Proto-Oncogene Proteins B-raf

Grants and funding

This research was supported by a National Health and Medical Research Council grant (NHMRC #1050455) and an Australian Postgraduate Award. DN was supported by a Cancer Australia grant #552449. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.