title: Refining molecular analysis in the pathways of colorectal carcinogenesis.
abstract: OBJECTIVE
  In the stepwise model, specific genetic and epigenetic changes accumulate as colorectal adenomas progress to carcinomas (CRCs). CRCs also acquire global phenotypes, particularly microsatellite instability (MSI) and aneuploidy/polyploidy (chromosomal instability, CIN). Few changes specific to MSI-low or CIN+ cancers have been established.
  
  
  METHODS
  We investigated 100 CRCs for: mutations and loss of heterozygosity (LOH) where appropriate, of APC, K-ras, BRAF, SMAD4, and p53; deletion on 5q around APC and 18q around SMAD4; total chromosomal-scale losses and gains; MSI; and CIN.
  
  
  RESULTS
  As expected, CIN- cancers had fewer chromosomal changes overall than CIN+ lesions, but after correcting for this, 5q deletions alone predicted CIN+ status. 5q deletions were not, however, significantly associated with APC mutations, which were equally frequent in CIN+ and CIN- tumors. We therefore found no evidence to show that mutant APC promotes CIN. p53 mutations/LOH were more common in CIN+ than CIN- lesions, and all chromosomal amplifications were in CIN+ tumors. CIN- cancers could be subdivided according to the total number of chromosomal-scale changes into CIN-low and CIN-stable groups; 18q deletion was the best predictor, being present in nearly all CIN-low lesions and almost no CIN-stable tumors. MSI-low was not associated with CIN, any specific mutation, a mutational signature, or clinicopathologic characteristic.
  
  
  CONCLUSIONS
  Overall, the components of the stepwise model (APC, K-ras, and p53 mutations, plus 18q LOH) tended to co-occur randomly. We propose an updated version of this model comprising 4 pathways of CRC pathogenesis, on the basis of 5q/18q deletions, MSI (high/low), and CIN (high/low/stable).
authors.affiliation: Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowan
authors.forename: Sarah
authors.initials: S
authors.lastname: Halford
authors.forename: Michelle
authors.initials: M
authors.lastname: Gaasenbeek
authors.forename: Zoe
authors.initials: Z
authors.lastname: Kemp
authors.forename: Oliver
authors.initials: O
authors.lastname: Sieber
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Volikos
authors.forename: Eleanor
authors.initials: E
authors.lastname: Douglas
authors.forename: Heike
authors.initials: H
authors.lastname: Fiegler
authors.forename: Nigel
authors.initials: N
authors.lastname: Carter
authors.forename: Ian
authors.initials: I
authors.lastname: Talbot
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D002277:Carcinoma / Q000235:genetics*; D043171:Chromosomal Instability; D002872:Chromosome Deletion; D015179:Colorectal Neoplasms / Q000235:genetics*; D018450:Disease Progression; D017491:Genes, APC / Q000502:physiology; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D009154:Mutation