title: hMLH1 promoter methylation and BRAF mutations in high-frequency microsatellite instability colorectal cancers not fulfilling the revised Bethesda guidelines.
abstract: OBJECTIVE
  Sporadic colorectal cancers with high-frequency microsatellite instability (MSI-H) are related to hypermethylation of mismatch repair (MMR) genes and a higher frequency of BRAF mutations than Lynch syndrome. We estimated the feasibility of hereditary colorectal cancer based on hMLH1 methylation and BRAF mutations.
  
  
  METHODS
  Between May 2005 and June 2011, we enrolled all 33 analyzed patients with MSI-H cancer (male:female, 23:10; mean age, 65.5 ± 9.4 years) from a prospectively maintained database that didn't match Bethesda guidelines and who had results of hMLH1 methylation and BRAF mutations.
  
  
  RESULTS
  Among the 33 patients, hMLH1 promoter methylation was observed in 36.4% (n = 12), and was not significantly related with clinicopathologic variables, including MLH1 expression. BRAF mutations were observed in 33.3% of the patients (n = 11). Four of 11 and five of 22 patients with MSI-H colon cancers were BRAF mutation (+)/hMLH1 promoter methylation (-) or BRAF mutation (-)/hMLH1 promoter methylation (+). Of the 33 patients, 21.2% were BRAF mutation (+)/hMLH1 promoter methylation (+), indicating sporadic cancers. Seventeen patients (51.5%) were BRAF mutation (-)/hMLH1 promoter methylation (-), and suggested Lynch syndrome.
  
  
  CONCLUSIONS
  Patients with MSI-H colorectal cancers not fulfilling the Bethesda guidelines possibly have hereditary colorectal cancers. Adding tests of hMLH1 promoter methylation and BRAF mutations can be useful to distinguish them from sporadic colorectal cancers.
authors.affiliation: Department of Surgery, Samsung Medical Center, Seoul, Korea.
authors.forename: Sang Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Surgery, Samsung Medical Center, Seoul, Korea.
authors.forename: Hyoung Ran
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Pathology, Samsung Medical Center, Seoul, Korea.
authors.forename: Seok Hyung
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Center for Clinical Research, Samsung Biomedical Research Institute, Seoul, Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Surgery, Samsung Medical Center, Seoul, Korea.
authors.forename: Yong Beom
authors.initials: YB
authors.lastname: Cho
authors.affiliation: Department of Surgery, Samsung Medical Center, Seoul, Korea.
authors.forename: Seong Hyeon
authors.initials: SH
authors.lastname: Yun
authors.affiliation: Department of Surgery, Samsung Medical Center, Seoul, Korea.
authors.forename: Woo Yong
authors.initials: WY
authors.lastname: Lee
authors.affiliation: Department of Surgery, Samsung Medical Center, Seoul, Korea.
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Kim
keywords: BRAF; Colorectal neoplasms; Hereditary colorectal cancer; hMLH1