title: Increased cancer predisposition in family members of colorectal cancer patients harboring the p.V600E BRAF mutation: a population-based study.
abstract: BACKGROUND
  The serrated pathway represents a distinct molecular pathway of colorectal carcinogenesis and is associated with the p.V600E BRAF mutation. The objective of this study is to characterize the cancer family history and clinicopathologic features of colorectal cancer (CRC) patients according to the microsatellite instability (MSI) and BRAF mutation status of their tumors.
  
  
  METHODS
  The tumors from 558 population-based CRC patients underwent pathologic examination and molecular analysis for MSI, BRAF, and germline mutations in mismatch repair genes MUTYH and APC. The cancer history in first-degree relatives (FDR) of index patients was ascertained.
  
  
  RESULTS
  The risk of CRC in FDRs of index patients with MSI-H BRAF mutation [hazard ratio (HR) = 2.49; 95% confidence interval (95% CI), 1.57- 3.93] and microsatellite-stable BRAF mutation tumors (HR = 1.64; 95% CI, 1.01-2.66) was significantly elevated compared with FDRs of index patients with microsatellite-stable BRAF wild-type tumors. The incidence of nonmelanoma skin cancer was also significantly elevated in FDRs of patients with BRAF mutation CRC (HR = 2.52; 95% CI, 1.31-4.86). Furthermore, BRAF mutation CRC was associated with a distinct clinical, molecular, and pathologic phenotype.
  
  
  CONCLUSIONS
  The increased incidence of cancer in FDRs of index CRC patients with the p.V600E BRAF mutation may be explained by a genetic predisposition to develop cancer through the serrated pathway of colorectal carcinogenesis.
  
  
  CONCLUSIONS
  Family members of BRAF CRC patients have an increased predisposition to develop cancer. Future work should aim to identify the causative genetic factors.
authors.affiliation: Health Sciences Centre, 300 Prince Philip Drive, St. John's, NL A1B3V6, Canada.
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Wish
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Hyde
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Parfrey
authors.forename: Jane S
authors.initials: JS
authors.lastname: Green
authors.forename: H Banfield
authors.initials: HB
authors.lastname: Younghusband
authors.forename: Michelle I
authors.initials: MI
authors.lastname: Simms
authors.forename: Dan G
authors.initials: DG
authors.lastname: Fontaine
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Dicks
authors.forename: Susan N
authors.initials: SN
authors.lastname: Stuckless
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: John R
authors.initials: JR
authors.lastname: McLaughlin
authors.forename: Michael O
authors.initials: MO
authors.lastname: Woods
authors.forename: Roger C
authors.initials: RC
authors.lastname: Green
mesh_terms: D000328:Adult; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase