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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2005-03-21

AUTHORS

Enric Domingo, Renée C Niessen, Carla Oliveira, Pia Alhopuro, Catia Moutinho, Eloi Espín, Manel Armengol, Rolf H Sijmons, Jan H Kleibeuker, Raquel Seruca, Lauri A Aaltonen, Kohzoh Imai, Hiroyuki Yamamoto, Simó Schwartz, Robert M W Hofstra

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. More... »

PAGES

3995-3998

Journal

TITLE

Oncogene

ISSUE

24

VOLUME

24

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1208569

DOI

http://dx.doi.org/10.1038/sj.onc.1208569

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1039376686

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/15782118


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