Mutational activation of the RAS‐RAF‐MAPK and the wnt pathway in small intestinal adenocarcinomas
- 1 January 2004
- journal article
- Published by Informa UK Limited in Scandinavian Journal of Gastroenterology
- Vol. 39 (8), 748-753
- https://doi.org/10.1080/00365520410005847
Abstract
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. 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. 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. 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.Keywords
This publication has 13 references indexed in Scilit:
- Immunohistochemical analysis of adenocarcinoma of the small intestine: a tissue microarray studyJournal of Clinical Pathology, 2003
- High frequency of BRAF mutations in neviNature Genetics, 2002
- RAF/RAS oncogenes and mismatch-repair statusNature, 2002
- Mutations of the BRAF gene in human cancerNature, 2002
- An insight into the genetic pathway of adenocarcinoma of the small intestineGut, 2002
- Genetics of adenocarcinomas of the small intestine: frequent deletions at chromosome 18q and mutations of the SMAD4 geneOncogene, 2002
- The ABC of APCHuman Molecular Genetics, 2001
- Activation of c-K-ras mutations in human gastrointestinal tumorsGastroenterology, 2000
- Frequent K-ras mutations in small bowel adenocarcinomasDigestive Diseases and Sciences, 1996
- Mortality in celiac diseaseGastroenterology, 1989