title: Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome.
abstract: OBJECTIVE
  Activating beta-catenin mutations in exon 3 have been implicated in colorectal tumorigenesis. Although reports to the contrary exist, it has been suggested that beta-catenin mutations occur more often in microsatellite unstable (MSI+) colorectal carcinomas, including hereditary non-polyposis colorectal cancer (HNPCC), as a consequence of defective DNA mismatch repair. We have analysed 337 colorectal carcinomas and adenomas, from both sporadic cases and HNPCC families, to provide an accurate assessment of beta-catenin mutation frequency in each tumour type.
  
  
  METHODS
  Direct sequencing of exon 3 of beta-catenin.
  
  
  RESULTS
  Mutations were rare in sporadic (1/83, 1.2%) and HNPCC adenomas (1/37, 2.7%). Most of the sporadic adenomas analysed (80%) were small (<1 cm), and our data therefore differ from a previous report of a much higher mutation frequency in small adenomas. No oncogenic beta-catenin mutations were identified in 34 MSI+ and 78 microsatellite stable (MSI-) sporadic colorectal cancers but a raised mutation frequency (8/44, 18.2%) was found in HNPCC cancers; this frequency was significantly higher than that in HNPCC adenomas (p=0.035) and in both MSI- (p<0.0001) and MSI+ (p=0.008) sporadic cancers. Mutations were more common in higher stage (Dukes' stages C and D) cancers (p=0.001).
  
  
  CONCLUSIONS
  Exon 3 beta-catenin mutations are associated specifically with malignant colorectal tumours in HNPCC; mutations appear not to result directly from deficient mismatch repair. Our data provide evidence that the genetic pathways of sporadic MSI+ and HNPCC cancers may be divergent, and indicate that mutations in the HNPCC pathway of colorectal tumorigenesis may be determined by selection, not simply by hypermutation.
authors.affiliation: Cancer Research UK, Colorectal Cancer Unit, St Mark's Hospital, Harrow, HA1 3UJ, UK.
authors.forename: V
authors.initials: V
authors.lastname: Johnson
authors.forename: E
authors.initials: E
authors.lastname: Volikos
authors.forename: S E
authors.initials: SE
authors.lastname: Halford
authors.forename: E T
authors.initials: ET
authors.lastname: Eftekhar Sadat
authors.forename: S
authors.initials: S
authors.lastname: Popat
authors.forename: I
authors.initials: I
authors.lastname: Talbot
authors.forename: K
authors.initials: K
authors.lastname: Truninger
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Jass
authors.forename: R
authors.initials: R
authors.lastname: Houlston
authors.forename: W
authors.initials: W
authors.lastname: Atkin
authors.forename: I P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: A R J
authors.initials: AR
authors.lastname: Silver
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D015534:Trans-Activators / Q000235:genetics*; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D015534:Trans-Activators; D051176:beta Catenin