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

Abstract

Background: The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMSs) 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 BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups.

Results: BRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P < 0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P = 0.013). BRAFV600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E 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 BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group.

Conclusions: BRAFV600E 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.

Figure 1.

Prognostic impact of KRAS and BRAF^V600E mutations in unstratified Oslo-series and according to MSI status. Kaplan–Meier survival curves showing 5-year overall survival (OS) for tumors with KRAS and BRAF^V600E mutations versus KRAS/BRAF wild-type in (A) the unstratified Oslo-series and (B) stratified according to MSI status. See supplementary Figure S5, available at Annals of Oncology online for analyses of 5-year relapse-free survival.

Figure 2.

BRAF ^V600E and KRAS mutations are associated with poor patient prognosis in specific CMS groups. (A) In 737 patients with stages I–IV CRC from two independent series (Oslo-series and GSE39582), 35 (5%) had MSS tumors of the CMS1 subtype. Among these patients, BRAF^V600E mutations were associated with a poor OS (left panel). No prognostic impact of BRAF^V600E mutations was seen in 97 patients with MSI tumors of the CMS1 subtype. (B) In the same set of patients, 341 (46%) had MSS tumors of the CMS2 subtype. Here, KRAS mutations were associated with a poor survival. (C) Analyzing undifferentiated (CMS1 and 4) and epithelial (CMS2 and 3) tumors within the MSS phenotype revealed KRAS mutations to have poor prognostic impact limited to epithelial tumors.