Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer

Background: The objective of the study was to examine the role of microsatellite instability (MSI) and BRAFV600Emutation in colorectal cancer (CRC) by categorising patients into more detailed subtypes based on tumour characteristics. Methods: Tumour samples from 762 population-based patients with sporadic CRC were analysed for MSI and BRAFV600E by immunohistochemistry. Patient survival was followed-up for a median of 5.2 years. Results: Compared with microsatellite stable (MSS) CRC, MSI was prognostic for better disease-free survival (DFS; 5 years: 85.8% vs 75.3%, 10 years: 85.8% vs 72.9%, P = 0.027; HR 0.49, CI 0.30-0.80, P = 0.005) and disease-specific survival (DSS; 5 years: 83.2% vs 70.5%; 10 years: 83.2 vs 65.0%, P = 0.004). Compared with BRAF wild type, BRAFV600E was a risk for poor survival (overall survival; 5 years: 62.3% vs 51.6%, P = 0.014; HR 1.43, CI 1.07-1.90, P = 0.009), especially in rectal cancer (for DSS, HR: 10.60, CI: 3.04-36.92, P<0.001). The MSS/BRAFV600E subtype was a risk for poor DSS (HR: 1.88, CI: 1.06-3.31, P = 0.030), but MSI/BRAFV600E was a prognostic factor for DFS (HR: 0.42, CI: 0.18-0.96, P = 0.039). Among stage I-II patients, the MSS/BRAFV600E subtype was independently associated with poor DSS (HR: 5.32, CI: 1.74-16.31, P = 0.003). Conclusions: Microsatellite instable tumours were associated with better prognosis compared with MSS. BRAFV600E was associated with poor prognosis unless it occurred together with MSI. The MSI/BRAFV600E subtype was a favourable prognostic factor compared with the MSS/BRAF wild-type subtype. BRAFV600E rectal tumours showed particularly poor prognosis. The MSS/BRAFV600E subtype was associated with increased disease-specific mortality even in stage I-II CRC.