Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: Prognostic implications and response to chemotherapy

Abstract

ObjectiveThe aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy.DesignThis retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS).ResultsPatients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P<0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05–2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P<0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24–3.44, P = 0.005).ConclusionWe confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.

Terminology, Molecular Features, Epidemiology, and Management of Serrated Colorectal Neoplasia

“…CRCs with BRAF mutations have high levels of CpG island methylation (CIMP-high), MSI, and are mainly found in the right colon. [39][40][41][42] MSI is found in conventional adenomas only in patients with Lynch syndrome (Dabir et al, unpublished data), so it is reasonable to assume that CRCs with BRAF mutations (3%-8% of CRCs) [39][40][41][42] are of only serrated origin, and are derived from SSLs. Morphologically, medullary, mucinous, and signet ring cell carcinomas are overrepresented in this tumor group.…”

“…A second group of colorectal tumors, which is more rare (account for 2%-6%), have mutations in BRAF, are CIMP high, but are microsatellite stable (MSS). [39][40][41][42] BRAF mutations are rare in conventional adenomas, 45,46 so most of these tumors are of serrated origin (from either SSLs or TSAs). The third group of colorectal tumors is characterized by KRAS mutations and MSS.…”

“…These account for 25%-33% of colorectal tumors. [39][40][41][42] Only a small proportion of these tumors are likely to be of serrated origin, given the relative rarity of the TSA precursor, and the fact that KRAS mutations are found more frequently in conventional adenomas. 45 However, most colorectal tumors (53%-70%) do not fall into any of these categories.…”

Feasibility Study of a Modified XELOX Adjuvant Chemotherapy for High-Recurrence Risk Patients With Operated Stage III Colon Cancer

“…Third, although the TNM stage is important for colon cancer management, it seems to be insufficient to determine the authentic high-risk patients with stage III colon cancer. Tumor molecular markers, such as CpG island methylator phenotype (CIMP) status; driver gene mutations, such as KRAS and BRAF; and tumor immune microenvironment, have been linked to different recurrence risks among stage III colon cancer patients (Auclin et al, 2017;Murcia et al, 2018). The above molecular data were unavailable in the current study.…”

Personalized Medicine—Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer

“…An example of this is observed in CIMP-H tumors found to be MSI-positive, harboring the BRAF mutation results in a good prognosis [41]. However, MSI-negative tumors which are positive for CIMP and the BRAF mutation have a poor prognosis [153] (Table 2). Thus, the independent value of CIMP needs to be validated before being clinically valuable.…”