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Objective  The 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.    Design  This 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).    Results  Patients 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).    Conclusion  We 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.

plos one

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