1. ¹Molecular Oncology and Aging Research, Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain
2. ²Department of Medical Genetics, University of Groningen, A Deusinglaan 4, 9713 AW Groningen, The Netherlands
3. ³Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-465 Porto, Portugal
4. ⁴Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
5. ⁵Department of Clinical Genetics, University Hospital Groningen, Groningen, The Netherlands
6. ⁶Department of Gastroenterology, University Hospital Groningen, Groningen, The Netherlands
7. ⁷First Department of Internal Medicine, Sapporo Medical University, S.1, W.16, Chuo-ku, Sapporo 060-8543, Japan

Correspondence: S Schwartz Jr, E-mail: sschwartz@vhebron.net

Received 19 October 2004; Revised 25 January 2005; Accepted 28 January 2005; Published online 21 March 2005.

Abstract

Recently, it was shown that the oncogenic activation of BRAF, a member of the RAS/RAF family of kinases, by the V600E mutation is characteristic for sporadic colon tumors with microsatellite instability. Further, it was shown to associate with the silencing of the mismatch repair (MMR) gene MLH1 by hypermethylation. Moreover, BRAF mutations proved to be absent in tumors from hereditary nonpolyposis colorectal cancer syndrome (HNPCC) families with germline mutations in the MMR genes MLH1 and MSH2. These data suggest that the oncogenic activation of BRAF is involved only in sporadic colorectal tumorigenesis. In order to further support this hypothesis, we have extended the analysis of the BRAF gene to a different subset of HNPCC families without germline mutations in MLH1 and MSH2. BRAF-V600E mutations were analysed by automatic sequencing in 38 tumors from HNPCC families with germline mutations in the MSH6 gene and also in HNPCC (suspected) families that do not have mutations in the MMR genes MLH1, MSH2 and MSH6. All patients belong to different families. No mutations were detected in 14 tumors from HNPCC patients with germline mutations in MSH6. Further, no mutations of BRAF were found in tumors from 23 MMR-negative families, from which 13 fulfilled the Amsterdam criteria (HNPCC) and 10 were suspected for HNPCC as they were positive for the Bethesda criteria. Overall, our data reinforce the concept that BRAF is not involved in the colorectal tumorigenesis of HNPCC. The detection of a positive BRAF-V600E mutation in a colorectal cancer suggests a sporadic origin of the disease and the absence of germline alterations of MLH1, MSH2 and also of MSH6. These findings have a potential impact in the genetic testing for HNPCC diagnostics and suggest a potential use of BRAF as exclusion criteria for HNPCC or as a molecular marker of sporadic cancer.