Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma.
Activation of the Raf/MEK/ERK (MAPK) signal transduction cascade by RAS mutations has been found in a variety of human cancers. Mutations of BRAF provide an alternative route for activation of this signalling pathway. To determine the role of mutations in BRAF and KRAS2 in the neoplastic progression of Barrett's adenocarcinoma, we analysed both genes for common mutations. After microdissection, DNA of 19 Barrett's adenocarcinomas, 56 Barrett's intraepithelial neoplasias (n=29 low-grade intraepithelial neoplasia (LGIN) and n=27 high-grade intraepithelial neoplasia (HGIN)), 30 Barrett's mucosa without neoplasia and normal squamous, as well as gastric epithelium, were analysed for BRAF and KRAS2 mutation. Activating BRAF mutations were identified in 2/19 Barrett's adenocarcinomas (11%) and in 1/27 HGIN (4%). KRAS2 mutations were found in four out of 19 (21%) Barrett's adenocarcinomas examined and in three cases of HGIN (11%). In LGIN as well as in normal gastric or oesophageal mucosa, neither BRAF nor KRAS2 mutations were detected. All lesions with KRAS2 mutations had an intact BRAF gene. The status of mismatch-repair proteins was neither related to BRAF nor KRAS2 mutations. These data indicate that RAS or BRAF mutations are detected in about 32% of all Barrett's adenocarcinomas. We conclude that the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett's adenocarcinoma.
Sommerer
Florian
F
Institute of Pathology, University of Leipzig, Liebigstrasse 26, Leipzig 04103, Germany.
Vieth
Michael
M
Markwarth
Annett
A
Röhrich
Knut
K
Vomschloss
Susanne
S
May
Andrea
A
Ell
Christian
C
Stolte
Manfred
M
Hengge
Ulrich R
UR
Wittekind
Christian
C
Tannapfel
Andrea
A
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics*; D001471:Barrett Esophagus / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins