title: Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation.
abstract: 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.
authors.affiliation: Molecular Pathology Program, Centre d'Investigacions en Bioquímica i Biologia Molecular, Barcelona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.forename: Eloi
authors.initials: E
authors.lastname: Espín
authors.forename: Manel
authors.initials: M
authors.lastname: Armengol
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: Mafalda
authors.initials: M
authors.lastname: Pinto
authors.forename: Alex
authors.initials: A
authors.lastname: Duval
authors.forename: Caroline
authors.initials: C
authors.lastname: Brennetot
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Richard
authors.initials: R
authors.lastname: Hamelin
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Simó
authors.initials: S
authors.lastname: Schwartz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology; D060466:Axin Protein; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000502:physiology; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004273:DNA, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000502:physiology; D009687:Nuclear Proteins; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism* / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D018631:ras Proteins
chemical_list: C491761:AXIN2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; C117307:KRAS protein, human; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D000070957:MutL Protein Homolog 1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins