Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation

BRAF, a serine/threonine kinase of the RAF family, is a downstream transducer of the RAS‐regulated MAPK pathway and signals upstream of MEK1/2 kinases. Recently, activating mutations within BRAF have been reported in a high percentage of melanomas and colorectal carcinomas and shown to have oncogeni...

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Veröffentlicht in:Genes chromosomes & cancer 2004-02, Vol.39 (2), p.138-142
Hauptverfasser: Domingo, Enric, Espín, Eloi, Armengol, Manel, Oliveira, Carla, Pinto, Mafalda, Duval, Alex, Brennetot, Caroline, Seruca, Raquel, Hamelin, Richard, Yamamoto, Hiroyuki, Schwartz Jr, Simó
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container_end_page 142
container_issue 2
container_start_page 138
container_title Genes chromosomes & cancer
container_volume 39
creator Domingo, Enric
Espín, Eloi
Armengol, Manel
Oliveira, Carla
Pinto, Mafalda
Duval, Alex
Brennetot, Caroline
Seruca, Raquel
Hamelin, Richard
Yamamoto, Hiroyuki
Schwartz Jr, Simó
description BRAF, a serine/threonine kinase of the RAF family, is a downstream transducer of the RAS‐regulated MAPK pathway and signals upstream of MEK1/2 kinases. Recently, activating mutations within BRAF have been reported in a high percentage of melanomas and colorectal carcinomas and shown to have oncogenic capabilities. Further, their association to mismatch‐repair‐deficient tumors has suggested the involvement of the RAS/RAF pathway in the tumorigenesis of microsatellite‐unstable colon cancers, and that RAS and RAF mutations are alternative genetic events. We determined whether colorectal mismatch‐repair‐deficient tumors with BRAF mutations show a specific genotype when compared with tumors with wild‐type BRAF, and whether they can be associated with a particular clinicopathological feature. Here, we report a striking association of BRAF, but not of APC, KRAS2, AXIN2, and TP53 mutations, with proximal mismatch‐repair‐deficient colon tumors and MLH1 hypermethylation. Our results support the hypothesis that proximal and distal colorectal tumors with mismatch repair deficiency harbor different genetic alterations, and we suggest that the involvement of the RAS/RAF pathway in colorectal tumorigenesis is differentially modulated according to tumor location and MLH1 inactivation. © 2003 Wiley‐Liss, Inc.
doi_str_mv 10.1002/gcc.10310
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subjects Adaptor Proteins, Signal Transducing
Adenomatous Polyposis Coli Protein - physiology
APC gene
Axin Protein
AXIN2 gene
Base Pair Mismatch - genetics
BRAF protein
Carrier Proteins
Colonic Neoplasms - enzymology
Colonic Neoplasms - etiology
Colonic Neoplasms - genetics
Cytoskeletal Proteins - physiology
DNA Methylation
DNA Repair - genetics
DNA Repair - physiology
DNA, Neoplasm - genetics
Enzyme Activation - genetics
Female
Genotype
Humans
KRAS2 gene
Male
MEK1 protein
MEK2 protein
mismatch repair
MLH1 protein
MutL Protein Homolog 1
Neoplasm Proteins - deficiency
Neoplasm Proteins - physiology
Nuclear Proteins
Phenotype
Proto-Oncogene Proteins - physiology
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf - metabolism
Proto-Oncogene Proteins c-raf - physiology
Proto-Oncogene Proteins p21(ras) - metabolism
raf protein
ras Proteins
TP53 gene
Tumor Suppressor Protein p53 - physiology
title Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation
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