CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer

Abstract

BACKGROUND

The prognostic impact of KRAS and BRAF^V600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMS) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups.

PATIENTS AND METHODS

Totally 1197 primary tumors from a Norwegian series of CRC stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAF^V600E mutations were used to evaluate differential impact of mutations on gene expression among CMS groups.

RESULTS

BRAF^V600E and KRAS mutations were both associated with inferior five-year overall survival (OS) exclusively in MSS tumors (BRAF^V600E mutation versus KRAS/BRAF wild-type: HR 2.85, P<0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P=0.013). BRAF^V600E mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAF^V600E mutation versus wild-type: HR 7.73, P=0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P=0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAF^V600E and KRAS mutations on gene expression signatures according to MSI-status and CMS group.

CONCLUSIONS

BRAF^V600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.