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

Abstract

Background: The objective of the study was to examine the role of microsatellite instability (MSI) and BRAF(V600E)mutation 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 BRAF(V600E) 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, BRAF(V600E) 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/BRAF(V600E) subtype was a risk for poor DSS (HR: 1.88, CI: 1.06-3.31, P=0.030), but MSI/BRAF(V600E) was a prognostic factor for DFS (HR: 0.42, CI: 0.18-0.96, P=0.039). Among stage I-II patients, the MSS/BRAF(V600E) 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. BRAF(V600E) was associated with poor prognosis unless it occurred together with MSI. The MSI/BRAF(V600E) subtype was a favourable prognostic factor compared with the MSS/BRAF wild-type subtype. BRAF(V600E) rectal tumours showed particularly poor prognosis. The MSS/BRAF(V600E) subtype was associated with increased disease-specific mortality even in stage I-II CRC.

Figure 1

(A) Colorectal cancer (CRC) disease-specific survival (DSS) of patients with microsatellite instable (MSI; n=111, green line) and with microsatellite stable (MSS) tumours (n=651, blue line). Five-year survival: MSI, 83.2%, MSS, 70.5%. Ten-year survival: MSI, 83.2% MSS, 65.0%. P=0.004 for log-rank test (Mantel–Cox). (B) Rectal cancer DSS of patients with BRAF^V600E (n=8, green line) and wild-type BRAF tumours (BRAF wild type, n=185, blue line). Five-year survival: BRAF wild type, 73.3% BRAF^V600E, 28.6%. Ten-year survival: BRAF wild type, 46.3% BRAF^V600E, 0%. P<0.001 for log-rank test (Mantel–Cox). (C) Colorectal cancer DSS of subtypes according to the following combinations of MSI and BRAF status: MSI/BRAF wild type (n=44, yellow line), MSI/BRAF^V600E (n=60, purple line), MSS/BRAF wild type (n=600, blue line), and MSS/BRAF^V600E (n=34, green line). Five-year survival: MSI/BRAF wild type, 80.7% MSI/ BRAF^V600E, 84.6% MSS/BRAF wild type, 72.8% MSS/BRAF^V600E, 40.5%. P<0.001 for log-rank test (Mantel–Cox). (D) Colorectal cancer DSS of patients with stage I–II disease according to the following combinations of MSI and BRAF status: MSI/BRAF wild type (n=33, yellow line), MSI/BRAF^V600E (n=35, purple line), MSS/BRAF wild type (n=329, blue line), and MSS/BRAF^V600E (n=9, green line). Five-year survival: MSI/BRAF wild type 93.4% MSI/BRAF^V600E 92.9% MSS/BRAF wild type 89.0% MSS/BRAF^V600E 70.0%. P=0.031 for log-rank test (Mantel–Cox); MSS/BRAF^V600E vs MSS/BRAF wild type.