Mutational activation of the RAS-RAF-MAPK and the Wnt pathway in small intestinal adenocarcinomas.
BACKGROUND
Adenocarcinomas of the small and the large intestine share risk factors and morphological features but both tumor types seem to follow different genetic pathways. The aim of this study on small intestinal carcinomas was to analyze alternative mechanisms of activation of pathways that are typically affected in colorectal cancer.


METHODS
Twenty-one sporadic carcinomas were investigated for mutations in KRAS, BRAF, the beta-catenin gene CTNNB1, and the mutational cluster region of APC. Immunohistochemical analysis was performed with a monoclonal antibody for beta-catenin, the transcriptionally active downstream component of wnt signaling.


RESULTS
Oncogene mutations were found in 13 (62%) small intestinal adenocarcinomas. Twelve tumors displayed a KRAS mutation, and a novel BRAF mutation at codon 603/604 was seen in one carcinoma without KRAS mutation. One tumor harbored a CTNNB1 mutation consisting of an insertion of 247 nucleotides deriving from chromosome 9. APC mutations were identified in 2 tumors. Immunohistochemistry demonstrated nuclear accumulation of beta-catenin in 5 carcinomas. These carcinomas included the tumor with a CTNNB1 mutation but not those with APC mutations.


CONCLUSIONS
Our data show frequent activation of the RAS-RAF-MAPK pathway through mutations of either KRAS or, infrequently, BRAF. Activation of the wnt pathway through accumulation of beta-catenin may have a role in a subset of small intestinal adenocarcinomas but in contrast to colorectal carcinoma, accumulation of beta-catenin is generally not caused by inactivating APC or activating CTNNB1 mutations.
Bläker
H
H
Institute of Pathology, University of Heidelberg, Germany. Hendrik_Blaeker@med.uni-heidelberg.de
Helmchen
B
B
Bönisch
A
A
Aulmann
S
S
Penzel
R
R
Otto
H F
HF
Rieker
R J
RJ
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D003598:Cytoskeletal Proteins / Q000032:analysis; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000032:analysis; D051153:Wnt Proteins; D051176:beta Catenin; D048490:raf Kinases / Q000235:genetics*
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases