In the present study we report the distribution and prognostic impact of KRAS and BRAF mutations according to microsatellite instability (MSI) status and consensus molecular subtypes (CMS) in colorectal cancer (CRC).
A total of 1197 primary tumor samples from a consecutive series of patients treated surgically for stage I-IV CRC at Oslo University Hospital, Norway, were included in the study. Comprehensive clinical and pathological data were prospectively collected for all patients. Mutation analyses were performed for hotspots in KRAS (exon 2: codon 12 and 13, exon 3: codon 61) and BRAF (exon 15: codon 600) and MSI-status was determined. A subset of samples were analyzed for gene expression using exon-level microarrays and classified according to the CMS groups of CRC, with confident classification obtained in 317 samples. To increase the number of samples with CMS classification the analysis was supplemented with gene expression data for 514 patients in the publically available dataset GSE39582, including also MSI status, BRAF and KRAS mutation status, as well as clinical data. Gene expression signatures previously shown to be associated with BRAF and KRAS mutations, respectively, were used to evaluate differential impact of mutations on gene expression among CMS groups.
BRAFV600E and KRAS mutations are shown to have inferior relapse-free survival in MSS tumors exclusively (BRAF mut vs KRAS/BRAF wt: Hazard ratio (HR) 2,35 (1,71-3,22); p
BRAFV600E mutations have poor prognostic value specific to MSS tumors in CMS1, while KRAS mutations are associated with adverse outcome in MSS tumors in CMS2.
Clinical trial identification
Legal entity responsible for the study
Oslo University Hospital
Norwegian Cancer Society, Research Council of Norway, Southern and Eastern Norway Regional Health Authority
All authors have declared no conflicts of interest.