Abstract 106: Chromosomal instability in BRAF mutant, microsatellite stable colorectal cancers

Abstract

Abstract BRAF mutant colorectal cancers can be stratified according to the presence of microsatellite instability (MSI). MSI cancers with a BRAF mutation are associated with an excellent patient prognosis. By contrast, in microsatellite stable (MSS) cancers, a BRAF mutation confers a very poor patient prognosis. The causes of such a detrimental outcome are yet to be thoroughly determined. We have previously reported that BRAF mutant, MSS cancers (BRAFmut/MSS) have a significantly higher rate of p53 mutation and present at more advanced stages than MSI cancers. Frequencies of these features in the BRAFmut/MSS cancers are similar to those observed in BRAF wild type, MSS cancers (BRAFwt/MSS). Chromosomal instability (CIN) is a dominant feature of BRAFwt/MSS cancers, whilst MSI cancers are considered to be diploid. In MSS cancers, CIN has been associated with a worse prognosis. We therefore hypothesised that CIN would be common in BRAF mutant/MSS cancers. BRAFmut/MSS (n=60), and BRAFwt/MSS cancers (n=90) were investigated for CIN using Loss of Heterozygosity (LOH) analysis over 12 loci encompassing chromosomal regions 5q, 8p, 17p and 18q. CIN was assigned if at least 1 marker was positive for LOH, and a cancer was reported as showing no loss if at least 5 markers were informative and none demonstrated LOH. CIN was frequently found in BRAFmut/MSS cancers (41/57, 72%), and this rate was comparable to that observed in BRAFwt/MSS cancers (74/90, 82%). The greatest rate of CIN in BRAFmut/MSS cancers occurred at 8p (26/44, 59%), and the least at 5q (19/49, 39%). BRAFwt/MSS cancers showed most CIN at 17p (43/65, 66.2%), and the least at 5q (43/80, 53.8%). Within the BRAFmut/MSS cancer subgroup, CIN was highly correlated with the CpG Island Methylator Phenotype (17/23, 74%). CIN in BRAFmut/MSS cancers was significantly predominant in those at advanced (15/17, 88%), compared to early AJCC stages of presentation (6/13, 46%) (p=0.02). BRAFmut/MSS cancers with CIN at 18q and 8p significantly associated with worse survival compared to those with no loss (p=0.003, p<0.05) when adjusted for stage. CIN at 5q, 8p and 18q in BRAFmut/MSS compared to BRAFwt/MSS cancers significantly correlated with poorer survival (p=0.002, p<0.001, p<0.001) when adjusted for stage. This study confirms that CIN is common in BRAFmut/MSS colorectal cancers, and indicates that extensive array based analyses of BRAF mutant cancers would be warranted. Moreover, it shows that CIN predominantly occurs in advanced BRAFmut/MSS cancers where it may contribute to poorer survival, and further highlights molecular similarities occurring between these and BRAFwt/MSS colorectal cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 106. doi:1538-7445.AM2012-106