BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes

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.

This work was supported by Grants from the Dutch Cancer Society (RUG 1997-1544 and RUG 2002-2678); the Spanish Fondo de Investigaciones Sanitarias (FlS 01/1350), Spain; the Ministry of

Education, Culture, Sports, Science, and Technology of Japan, and by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor,

and Welfare of Japan; and the Fundação para a Ciēncia e Tecnologia (POCTI/SAU-OBS/56921/2004), Portugal. ED was supported by a fellowship from the Spanish Fondo de Investigaciones

Sanitarias.

Molecular 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

Enric Domingo, Eloi Espín, Manel Armengol & Simó Schwartz Jr

Department of Medical Genetics, University of Groningen, A Deusinglaan 4, 9713 AW, Groningen, The Netherlands

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-465, Porto, Portugal

Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland

Department of Clinical Genetics, University Hospital Groningen, Groningen, The Netherlands

Department of Gastroenterology, University Hospital Groningen, Groningen, The Netherlands

First Department of Internal Medicine, Sapporo Medical University, S.1, W.16, Chuo-ku, Sapporo, 060-8543, Japan

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