title: Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum.
abstract: OBJECTIVE
  Colorectal cancer has been described in association with hyperplastic polyposis but the mechanism underlying this observation is unknown. The aim of this study was to characterise foci of dysplasia developing in the polyps of subjects with hyperplastic polyposis on the basis of DNA microsatellite status and expression of the DNA mismatch repair proteins hMLH1, hMSH2, and hMSH6.
  
  
  METHODS
  The material was derived from four patients with hyperplastic polyposis and between one and six synchronous colorectal cancers. Normal (four), hyperplastic (13), dysplastic (13), and malignant (11) samples were microdissected and a PCR based approach was used to identify mutations at 10 microsatellite loci, TGFbetaIIR, IGF2R, BAX, MSH3, and MSH6. Microsatellite instability-high (MSI-H) was diagnosed when 40% or more of the microsatellite loci showed mutational bandshifts. Serial sections were stained for hMLH1, hMSH2, and hMSH6.
  
  
  RESULTS
  DNA microsatellite instability was found in 1/13 (8%) hyperplastic samples, in 7/13 (54%) dysplastic foci, and in 8/11 (73%) cancers. None of the MSI-low (MSI-L) samples (one hyperplastic, three dysplastic, two cancers) showed loss of hMLH1 expression. All four MSI-H dysplastic foci and six MSI-H cancers showed loss of hMLH1 expression. Loss of hMLH1 in MSI-H but not in MSI-L lesions showing dysplasia or cancer was significant (p<0.001, Fisher's exact test). Loss of hMSH6 occurred in one MSI-H cancer and one MSS focus of dysplasia which also showed loss of hMLH1 staining.
  
  
  CONCLUSIONS
  Neoplastic changes in hyperplastic polyposis may occur within a hyperplastic polyp. Neoplasia may be driven by DNA instability that is present to a low (MSI-L) or high (MSI-H) degree. MSI-H but not MSI-L dysplastic foci are associated with loss of hMLH1 expression. At least two mutator pathways drive neoplasia in hyperplastic polyposis. The role of the hyperplastic polyp in the histogenesis of sporadic DNA microsatellite unstable colorectal cancer should be examined.
authors.affiliation: Department of Pathology, University of Queensland, Mayne Medical School, Herston, Australia. j.jass@mailbox.uq.edu.au
authors.forename: J R
authors.initials: JR
authors.lastname: Jass
authors.forename: H
authors.initials: H
authors.lastname: Iino
authors.forename: A
authors.initials: A
authors.lastname: Ruszkiewicz
authors.forename: D
authors.initials: D
authors.lastname: Painter
authors.forename: M J
authors.initials: MJ
authors.lastname: Solomon
authors.forename: D J
authors.initials: DJ
authors.lastname: Koorey
authors.forename: D
authors.initials: D
authors.lastname: Cohn
authors.forename: K L
authors.initials: KL
authors.lastname: Furlong
authors.forename: M D
authors.initials: MD
authors.lastname: Walsh
authors.forename: J
authors.initials: J
authors.lastname: Palazzo
authors.forename: T B
authors.initials: TB
authors.lastname: Edmonston
authors.forename: R
authors.initials: R
authors.lastname: Fishel
authors.forename: J
authors.initials: J
authors.lastname: Young
authors.forename: B A
authors.initials: BA
authors.lastname: Leggett
mesh_terms: D000368:Aged; D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D007417:Intestinal Polyps / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm