title: Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations.
abstract: OBJECTIVE
  Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC). Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of "double-negative" (MSI-/CIN-) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specific molecular changes, such as mutations in KRAS and BRAF, that have been associated with prognosis. It is not known which of MSI, CIN, and the specific gene mutations are primary predictors of survival.
  
  
  METHODS
  We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS, NRAS, BRAF, PIK3CA, FBXW7, and TP53, and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II/III CRC. We followed up promising associations in an Australian community-based cohort (N=375).
  
  
  RESULTS
  In the VICTOR patients, no specific mutation was associated with DFS, but individually MSI and CIN showed significant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR)=0.58, 95% confidence interval (CI) 0.36-0.93, and P=0.021; for CIN, HR=1.54, 95% CI 1.14-2.08, and P=0.005), and joint CIN/MSI testing significantly improved the prognostic prediction of MSI alone (P=0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN+/- variable. All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio.
  
  
  CONCLUSIONS
  MSI and CIN are independent predictors of DFS for stage II/III CRC. Prognostic molecular tests for CRC relapse should currently use MSI and a quantitative measure of CIN rather than specific gene mutations.
authors.affiliation: 1] Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Parkville, Victoria, Australia [2] Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Mouradov
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jorissen
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.forename: Pik Ying
authors.initials: PY
authors.lastname: Soo
authors.forename: Lara
authors.initials: L
authors.lastname: Lipton
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.forename: Havard E
authors.initials: HE
authors.lastname: Danielsen
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.forename: Christopher
authors.initials: C
authors.lastname: Yau
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Holmes
authors.forename: Ian T
authors.initials: IT
authors.lastname: Jones
authors.forename: Stephen
authors.initials: S
authors.lastname: McLaughlin
authors.forename: Peter
authors.initials: P
authors.lastname: Molloy
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hawkins
authors.forename: Robyn
authors.initials: R
authors.lastname: Ward
authors.forename: Rachel
authors.initials: R
authors.lastname: Midgely
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000235:genetics; D002869:Chromosome Aberrations; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins