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 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.

Colorectal cancer carcinogenesis: a review of mechanisms

“…The same finding is obtained in 15% of LS cases, which makes differentiation from sporadic CRCs difficult 101 . In such cases, the V600E mutation in v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) gene eliminates the possibility of LS 102 .…”

Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer

“…Given that there is increasing evidence the BRAFV600E mutant microsatellite stable tumours are a particularly poor prognostic group, [22][23][24][25][26][27][28] we attempted to further stratify mucinous MMRp tumours on the basis of BRAF status. Interestingly, and perhaps unexpectedly, we found similar 5-year survival rates for BRAF wild type (57%) and BRAFV600E mutant (51%) MMRp mucinous colorectal cancers (P = 0.610).…”

Comprehensive Analysis of the Relationship Between RAS and RAF Mutations and MSI Status of Colorectal Cancer in Northeastern China

“…Hence, it is lower than other cohorts previously reported in China (Table 4). In Western European countries [33][34][35][36][37][38][39][40][43][44], most studies demonstrated that the RAF mutation rate was over 10%. In the United States, only a few studies demonstrated a higher mutation rate of RAF [15][16][17]45].…”

“…The frequency of RAF mutation in various countries is 3-8 times higher in colon cancer than in rectal cancer [23,44]. The ratio of involvement is almost 2-5 times on the right compared to the left [43]. Besides, BRAF has an obvious relationship with tumor position and sex, and is also associated with highgrade tumors, mucous adenocarcinoma, and lymph node metastases.…”

“…In addition, MSI-H status is also related to [48][49][50][51], the frequency of MSI-H status is 10 times higher in colon cancer than in rectal cancer and 2-5 times higher in the right colon than in the left colon. In Europe, MSI-H occurs in about 15-20% of all CRCs [33,43,51]. In the United States, it occurs in about 10-15% of all CRCs.…”