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

Abstract

668 Background: 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. Methods: 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). Conclusions: 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.

Gene mutation profiling in Chinese colorectal cancer patients and its association with clinicopathological characteristics and prognosis

“…Some literature shows that MSI status may not have a prognostic relevance in CRC, but Yang et al suggested that microsatellite stable (MSS) + BRAF mutation was a poor prognostic factor, while MSI + BRAF mutation was related to a moderate prognosis, and MSS/MSI + BRAF wild type was associated with a more favorable outcome . Murcia et al reported a similar result, which suggested that the combination of MSS, BRAF mutation and CIMP positive related to poor prognosis . As there are few researches on the relationship between MSI status and gene mutation, more attention on this issue is needed.…”

Lymphovascular invasion represents a superior prognostic and predictive pathological factor of the duration of adjuvant chemotherapy for stage III colon cancer patients

“…Second, the median 56 months follow-up duration had insu cient power to calculate 5-year survival outcomes, which might result in a misestimation of the effect of LVI and PNI on OS. Additionally, tumor molecular markers, such as the microsatellite status, the 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 of stage III colon cancer [31,32]. The above molecular data were unavailable in current study.…”

Aberrant DNA methylation patterns in microsatellite stable human colorectal cancers define a new marker panel for the CpG island methylator phenotype

“…The observation that CIMP in our cohort of CRC correlated with either KRAS or BRAF mutation, which belong to one same pathway, suggests that this genetic defect is directly linked to the yet unknown mechanisms responsible for CIMP aberrant DNA methylation profile. Global profiling studies as well as studies focusing on defined CIMP marker panels have identified similar genotype/epigenotype relationships 18‐22 …”