Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers

Abstract

Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2-3 mutation status was assessed in 143 stage II (n 5 85) and III (n 5 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer-specific (CSS) and overall survival (OS) was analyzed using Kaplan-Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n 5 73) and KRAS mutations in 16% of cases (n 5 23). Patients with double wild-type cancers (dWT; i.e., BRAF and KRAS wild-type) had a highly favourable survival with 5-year CSS of 93% (95% CI 84-100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5-year CSS of 76% (95% CI 67-85%). In the subgroup of stage II patients with dWT cancers no cancer-specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.Colorectal cancer (CRC) is both clinically and biologically a heterogeneous disease. Microsatellite instability (MSI) occurs in 15% of CRC and results from a genetic or epigenetic defect in DNA mismatch repair (MMR), occurring sporadically (12%) or due to Lynch syndrome (3%). These cancers are more frequently right sided and often show poor differentiation, increased mucin formation and lymphocytic infiltration. 1 The crucial RAS-RAF-MEK-ERK signal transduction pathway is affected in both MSS and MSI CRC, and can be

Microsatellite Instability and Survival in Stage II Colorectal Cancer: A Systematic Review and Meta-analysis

“…The role of BRAF mutations was presented only in 8 studies of this metaanalysis (range=7.9-56.7%), but only in 2 studies MSI status was confirmed to be an independent positive predictor of OS with respect to BRAF mutations in the multivariate analysis. Overall, the role of BRAF mutations in early CRC is, however, still debated in MSI stage II CRC (59)(60)(61). Recently, CRC subtypes have been proposed based on distinct global gene expression profiles.…”

The Clinical Impact of the Genomic Landscape of Mismatch Repair–Deficient Cancers

“…MMRd might have an infl uence on the prognostic impact of other molecular variables. For example, the BRAF V600E mutation, which is highly prevalent in sporadic but not Lynch syndrome-related MSI colorectal cancers, is a negative prognostic factor in colorectal cancer ( 31 ); however, a recent analysis of more than 4,000 patients who underwent adjuvant therapy demonstrated that BRAF status has no correlation with prognosis for MSI patients ( 32 ).…”

Loss of KCNQ1 expression in stage II and stage III colon cancer is a strong prognostic factor for disease recurrence

“…One example of such a biomarker is microsatellite instability (MSI), which is associated with a more favourable prognosis in stages I and II disease compared with microsatellite stable (MSS) tumours (Sinicrope et al , 2006; Vilar and Gruber, 2010; Sinicrope and Sargent, 2012; de Cuba et al , 2015). Within the group of MSS patients, which comprises 80–85% of all CRCs, there are still major differences in survival, so further stratification is needed for adequate selection of patients who may benefit from adjuvant chemotherapy.…”