title: Molecular subtypes in stage II-III colon cancer defined by genomic instability: early recurrence-risk associated with a high copy-number variation and loss of RUNX3 and CDKN2A.
abstract: OBJECTIVE
  We sought to investigate various molecular subtypes defined by genomic instability that may be related to early death and recurrence in colon cancer.
  
  
  METHODS
  We sought to investigate various molecular subtypes defined by instability at microsatellites (MSI), changes in methylation patterns (CpG island methylator phenotype, CIMP) or copy number variation (CNV) in 8 genes. Stage II-III colon cancers (n = 64) were investigated by methylation-specific multiplex ligated probe amplification (MS-MLPA). Correlation of CNV, CIMP and MSI, with mutations in KRAS and BRAFV600E were assessed for overlap in molecular subtypes and early recurrence risk by uni- and multivariate regression.
  
  
  RESULTS
  The CIMP phenotype occurred in 34% (22/64) and MSI in 27% (16/60) of the tumors, with noted CIMP/MSI overlap. Among the molecular subtypes, a high CNV phenotype had an associated odds ratio (OR) for recurrence of 3.2 (95% CI 1.1-9.3; P = 0.026). Losses of CACNA1G (OR of 2.9, 95% CI 1.4-6.0; P = 0.001), IGF2 (OR of 4.3, 95% CI 1.1-15.8; P = 0.007), CDKN2A (p16) (OR of 2.0, 95% CI 1.1-3.6; P = 0.024), and RUNX3 (OR of 3.4, 95% CI 1.3-8.7; P = 0.002) were associated with early recurrence, while MSI, CIMP, KRAS or BRAF V600E mutations were not. The CNV was significantly higher in deceased patients (CNV in 6 of 8) compared to survivors (CNV in 3 of 8). Only stage and loss of RUNX3 and CDKN2A were significant in the multivariable risk-model for early recurrence.
  
  
  CONCLUSIONS
  A high copy number variation phenotype is a strong predictor of early recurrence and death, and may indicate a dose-dependent relationship between genetic instability and outcome. Loss of tumor suppressors RUNX3 and CDKN2A were related to recurrence-risk and warrants further investigation.
authors: Centre of Organelle Research (CORE), University of Stavanger, Stavanger, Norway; Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.
authors: Marianne
authors: M
authors: Berg
authors: Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway.
authors: Oddmund
authors: O
authors: Nordgaard
authors: Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Hartwig
authors: H
authors: Kørner
authors: Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway.
authors: Satu
authors: S
authors: Oltedal
authors: Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway.
authors: Rune
authors: R
authors: Smaaland
authors: Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Jon Arne
authors: JA
authors: Søreide
authors: Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors: Kjetil
authors: K
authors: Søreide
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000235:genetics*; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D019942:Genes, p16; D042822:Genomic Instability; D006801:Humans; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016019:Survival Analysis
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human