title: A novel classification of colorectal tumors based on microsatellite instability, the CpG island methylator phenotype and chromosomal instability: implications for prognosis.
abstract: BACKGROUND
  We studied the overlap between the major (epi)genomic events microsatellite instability (MSI), the CpG island methylator phenotype (CIMP) and chromosomal instability (CIN) in colorectal cancer (CRC), and whether specific (epi)genotypes were associated with CRC-related deaths.
  
  
  METHODS
  Molecular analyses using tumor DNA were successful in 509 CRC cases identified within the Netherlands Cohort Study in the period 1989-1993. Follow-up for the vital status until May 2005 was 100%.
  
  
  RESULTS
  MSI (12.6%), CIMP-only (5.3%), CIMP + CIN (13.4%), CIN-only (58.2%) and triple-negative tumors (10.6%) differed significantly regarding tumor localization, differentiation grade, initial adjuvant therapy (AT) use and genetic characteristics (P ≤ 0.03). CIMP-only, CIMP + CIN and triple-negative tumors, compared with CIN-only tumors, were significantly associated with a 3.67, 2.44 and 3.78-fold risk of CRC-related deaths after 2-year follow-up (95% confidence intervals, CIs, 1.70-7.91, 1.35-4.41 and 1.97-7.25, respectively), but not after late follow-up. MSI tumors were borderline significantly associated with a 0.40-fold risk of CRC-related deaths after late follow-up (95% CI 0.15-1.03).
  
  
  CONCLUSIONS
  This is the first study to show that specific (epi)genotypes may hold a differential prognostic value that may vary over time. Although no specific treatment data were available, an explanation for the differential findings over time might be that (epi)genotypes modify therapy response.
authors.affiliation: Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: C C J M
authors.initials: CC
authors.lastname: Simons
authors.forename: L A E
authors.initials: LA
authors.lastname: Hughes
authors.forename: K M
authors.initials: KM
authors.lastname: Smits
authors.forename: C A
authors.initials: CA
authors.lastname: Khalid-de Bakker
authors.forename: A P
authors.initials: AP
authors.lastname: de Bruïne
authors.forename: B
authors.initials: B
authors.lastname: Carvalho
authors.forename: G A
authors.initials: GA
authors.lastname: Meijer
authors.forename: L J
authors.initials: LJ
authors.lastname: Schouten
authors.forename: P A
authors.initials: PA
authors.lastname: van den Brandt
authors.forename: M P
authors.initials: MP
authors.lastname: Weijenberg
authors.forename: M
authors.initials: M
authors.lastname: van Engeland
mesh_terms: D000368:Aged; D043171:Chromosomal Instability / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011379:Prognosis; D011795:Surveys and Questionnaires
keywords: chromosomal instability; colorectal neoplasms; methylation; microsatellite instability; prognosis