title: Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer.
abstract: OBJECTIVE
  Recently, an alternative pathway of tumorigenesis has been identified in the colorectum associated with serrated precursor lesions, variable levels of microsatellite instability (MSI-V), and driven in part by activating mutations in the BRAF proto-oncogene (V599E). Somatic BRAF mutations in hereditary nonpolyposis colon cancer (HNPCC) are rarely observed. Here, we discuss their role in the development of other familial colorectal cancers (CRC). We studied non-FAP, non-HNPCC CRC families characterized by tumors that varied in their level of MSI between individual members.
  
  
  METHODS
  A subset of tumors from a total of 55 collected (25 polyps and 30 cancers) from 43 individuals across 11 families underwent pathology review, examination for V599E using allele-specific polymerase chain reaction, and for methylation of the MINT31 CpG island.
  
  
  RESULTS
  All MSI-V families met the current revised Bethesda Guidelines and 6 of 11 (55%) met the Amsterdam I criteria. V599E was observed in 12 of 19 (63%) polyps and 14 of 20 (70%) cancers (4 of 4 high MSI, 2 of 4 low MSI, and 8 of 12 stable MSI), a significant increase over HNPCC (0 of 15 or 0%), and unselected CRC (30 of 197 or 15.2%) ( P < .05). Eight of the 10 (80%) cancers that underwent analysis showed hypermethylation of MINT31. CRCs showed early age at onset and were more likely to show a serrated architecture than unselected CRCs ( P < .05).
  
  
  CONCLUSIONS
  These data provide evidence that the families described here represent a syndrome of familial CRC that is distinct from HNPCC. High levels of BRAF mutation and MINT31 hypermethylation suggest an origin in the serrated pathway of CRC development.
authors.affiliation: Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research, Herston, Australia. joanneY@qimr.edu.au
authors.forename: Joanne
authors.initials: J
authors.lastname: Young
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Barker
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Simms
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Kelli G
authors.initials: KG
authors.lastname: Biden
authors.forename: Daniel
authors.initials: D
authors.lastname: Buchanan
authors.forename: Ron
authors.initials: R
authors.lastname: Buttenshaw
authors.forename: Vicki L J
authors.initials: VL
authors.lastname: Whitehall
authors.forename: Sven
authors.initials: S
authors.lastname: Arnold
authors.forename: Leigh
authors.initials: L
authors.lastname: Jackson
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kambara
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Spring
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Walker
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leggett
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf