title: BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors.
abstract: BACKGROUND
  Alterations of BRAF have been implicated in the carcinogenesis of colorectal tumors with microsatellite instability (MSI). These alterations were attributed to defective DNA mismatch repair, which underlies MSI. It was the objective of this study to clarify the role of BRAF in colorectal carcinoma with MSI.
  
  
  METHODS
  After sequencing for BRAF and KRAS in 82 colorectal tumor samples with or without MSI, mismatch repair protein expression was analyzed by immunohistochemistry, and promoter methylation of hMLH1 was analyzed with a methylation-specific polymerase chain reaction. Results were correlated with the germline status of hMLH1 or hMSH2 and clinical characteristics.
  
  
  RESULTS
  BRAF was mutated more often in tumors with MSI than in tumors without MSI (27% vs. 5%; P = 0.016). The most prevalent BRAF alteration, V599E, occurred only in tumors with MSI. BRAF V599E was associated with more frequent hMLH1 promoter methylation (P = 0.07) and loss of hMLH1 (P = 0.02). The median age of patients with BRAF V599E was older compared with the median age of patients without this mutation (P = 0.001; 78 vs. 49 yrs). No BRAF alterations occurred in patients with germline mutations of mismatch repair genes. Five novel BRAF mutations were identified.
  
  
  CONCLUSIONS
  Although BRAF V599E was common in colorectal carcinomas with MSI, it was not a consequence of deficient mismatch repair. The current data showed instead that the BRAF V599E mutation was associated only with a subgroup of colorectal carcinomas with MSI that were obtained from older patients without hereditary nonpolyposis colorectal carcinoma and showed epigenetic silencing of hMLH1. These results indicated that tumors with MSI caused by epigenetic MLH1 silencing have a distinct mutational background from that of tumors with genetic loss of mismatch repair, suggesting that there are two genetically distinct entities of microsatellite-instable tumors.
authors: 2nd Department of Internal Medicine, Saarland University Hospital, Homburg/Saar, Germany.
authors: Nikolaus
authors: N
authors: Lubomierski
authors: Guido
authors: G
authors: Plotz
authors: Marc
authors: M
authors: Wormek
authors: Knut
authors: K
authors: Engels
authors: Susanne
authors: S
authors: Kriener
authors: Jorg
authors: J
authors: Trojan
authors: Bernd
authors: B
authors: Jungling
authors: Stefan
authors: S
authors: Zeuzem
authors: Jochen
authors: J
authors: Raedle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein