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 = 85) and III (n = 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 = 73) and KRAS mutations in 16% of cases (n = 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. What's new? Mutations in the BRAF and KRAS genes are widely studied in patients with colorectal carcinomas (CRC), but their prognostic impact in cancers characterized by microsatellite instability due to impaired DNA mismatch repair remains unclear. Here the authors show that both mutations are associated with poor survival in patients afflicted with these genetically hypermutatable tumors as compared to patients carrying tumors with wildtype BRAF and KRAS genes, underscoring the prognostic value of determining combined or single mutations in these genes in this subset of CRC patients.

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Keywords BRAF, colon cancer, KRAS, microsatellite instability, survival
Persistent URL dx.doi.org/10.1002/ijc.29855, hdl.handle.net/1765/89618
Journal International Journal of Cancer
De Cuba, E.M.V, Snaebjornsson, P, Heideman, D.A.M, Grieken, N.C.T, Bosch, L.J.W, Fijneman, R.J.A, … Meijer, G.A. (2016). Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers. International Journal of Cancer, 138(5), 1139–1145. doi:10.1002/ijc.29855