title: Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer.
abstract: BACKGROUND
  The objective of the study was to examine the role of microsatellite instability (MSI) and BRAF(V600E)mutation in colorectal cancer (CRC) by categorising patients into more detailed subtypes based on tumour characteristics.
  
  
  METHODS
  Tumour samples from 762 population-based patients with sporadic CRC were analysed for MSI and BRAF(V600E) by immunohistochemistry. Patient survival was followed-up for a median of 5.2 years.
  
  
  RESULTS
  Compared with microsatellite stable (MSS) CRC, MSI was prognostic for better disease-free survival (DFS; 5 years: 85.8% vs 75.3%, 10 years: 85.8% vs 72.9%, P=0.027; HR 0.49, CI 0.30-0.80, P=0.005) and disease-specific survival (DSS; 5 years: 83.2% vs 70.5%; 10 years: 83.2 vs 65.0%, P=0.004). Compared with BRAF wild type, BRAF(V600E) was a risk for poor survival (overall survival; 5 years: 62.3% vs 51.6%, P=0.014; HR 1.43, CI 1.07-1.90, P=0.009), especially in rectal cancer (for DSS, HR: 10.60, CI: 3.04-36.92, P<0.001). The MSS/BRAF(V600E) subtype was a risk for poor DSS (HR: 1.88, CI: 1.06-3.31, P=0.030), but MSI/BRAF(V600E) was a prognostic factor for DFS (HR: 0.42, CI: 0.18-0.96, P=0.039). Among stage I-II patients, the MSS/BRAF(V600E) subtype was independently associated with poor DSS (HR: 5.32, CI: 1.74-16.31, P=0.003).
  
  
  CONCLUSIONS
  Microsatellite instable tumours were associated with better prognosis compared with MSS. BRAF(V600E) was associated with poor prognosis unless it occurred together with MSI. The MSI/BRAF(V600E) subtype was a favourable prognostic factor compared with the MSS/BRAF wild-type subtype. BRAF(V600E) rectal tumours showed particularly poor prognosis. The MSS/BRAF(V600E) subtype was associated with increased disease-specific mortality even in stage I-II CRC.
authors.affiliation: Department of Surgery, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: T T
authors.initials: TT
authors.lastname: Seppälä
authors.affiliation: Department of Pathology, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: J P
authors.initials: JP
authors.lastname: Böhm
authors.affiliation: Department of Pathology, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Friman
authors.affiliation: Department of Pathology, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Lahtinen
authors.affiliation: Department of Surgery, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: V M J
authors.initials: VM
authors.lastname: Väyrynen
authors.affiliation: Department of Surgery, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: T K E
authors.initials: TK
authors.lastname: Liipo
authors.affiliation: 1] Unit of Pathology and Genetics, HUSLAB, Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland [2] Department of Pathology and Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
authors.forename: A P
authors.initials: AP
authors.lastname: Ristimäki
authors.affiliation: Department of Surgery, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: M V J
authors.initials: MV
authors.lastname: Kairaluoma
authors.affiliation: Department of Surgery, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: I H
authors.initials: IH
authors.lastname: Kellokumpu
authors.affiliation: Department of Pathology, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: T H I
authors.initials: TH
authors.lastname: Kuopio
authors.affiliation: Department of Surgery, Central Finland Central Hospital, Keskussairaalantie 19, 40620 Jyväskylä, Finland.
authors.forename: J-P
authors.initials: JP
authors.lastname: Mecklin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf