title: 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 = 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.
authors.affiliation: Department of Surgical Oncology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: E M V
authors.initials: EM
authors.lastname: de Cuba
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Snaebjornsson
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: D A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: N C T
authors.initials: NC
authors.lastname: van Grieken
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: L J W
authors.initials: LJ
authors.lastname: Bosch
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: R J A
authors.initials: RJ
authors.lastname: Fijneman
authors.affiliation: Department of Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Belt
authors.affiliation: Department of Pathology, Kennemer Gasthuis, Haarlem, the Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Bril
authors.affiliation: Department of Surgery, Kennemer Gasthuis, Haarlem, the Netherlands.
authors.forename: H B A C
authors.initials: HB
authors.lastname: Stockmann
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Hooijberg
authors.affiliation: Department of Medical Oncology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands.
authors.forename: C J A
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Koopman
authors.affiliation: Department of Pathology, University Medical Center St. Radboud, Nijmegen, the Netherlands.
authors.forename: I D
authors.initials: ID
authors.lastname: Nagtegaal
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: V H M
authors.initials: VH
authors.lastname: Coupé
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Carvalho
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: Meijer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF; KRAS; colon cancer; microsatellite instability; survival