Abstract 3170: BRAF expression is associated with poor survival in colorectal cancers independent of BRAF (V600E) mutation

Abstract

Abstract The RAS pathway is known to be commonly activated and a key determinant of colorectal cancer (CRC) biology, with mutational activation of RAS/RAF genes observed in ~50% of CRC patients. The relationship between gene mutation and expression is, however, poorly understood. We analyzed how the expression of RAS/RAF genes vs. their respective mutations impacted outcomes. The relationship to other rarely mutated RAS/RAF genes (HRAS, ARAF, RAF1 (i.e. c-RAF)) was also examined in these tumors. While KRAS expression was positively associated with KRAS mutations (r=0.26, p<0.0001), BRAF expression was, unexpectedly, negativelycorrelated with BRAF (V600E) mutation (r= -0.18, p=0.0001). Thus, a substantial number of patients express relatively high levels of BRAF absent of BRAF mutations. Additional analysis indicates that lower BRAF expression was significantly correlated with MSI or the CMS1 subtype that is strongly associated with BRAF (V600E). Intriguingly, despite negative association with mutant BRAF (V600E) that is well-established to be associated with poor prognosis, higher BRAF expression was also associated with poor overall survival, as indicated by Kaplan-Meier survival analysis of BRAF expression by quartiles in either 458 CRCs (Logrank test for trend p=0.0262) in 406 WT BRAF CRCs (p=0.0102). Note that the expression of all other five RAS/RAF genes (HRAS, KRAS, NRAS, ARAF and RAF1) was not associated with survival. Further analysis with the gene expression signatures measuring RAS pathway activation reveals that unlike BRAF (V600E) (or KRAS mutations or KRASexpression), BRAF expression appeared to be negatively correlated with RAS pathway activation signature scores. Taken together, these data suggest that higher BRAF expression in CRC patients may activate an “alternative” pathway to the canonical pathway directed by mutant BRAF (V600E) as yet another means to deliver tumor progression. Citation Format: Mingli Yang, Michael J. Schell, Timothy J. Yeatman. BRAF expression is associated with poor survival in colorectal cancers independent of BRAF (V600E) mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3170.