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Large‐scale N‐terminal deletions but not point mutations stabilize β‐catenin in small bowel carcinomas, suggesting divergent molecular pathways of small and large intestinal carcinogenesis
Author(s) -
Breuhahn K,
Singh S,
Schirmacher P,
Bläker H
Publication year - 2008
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2362
Subject(s) - adenomatous polyposis coli , carcinogenesis , catenin , biology , point mutation , wnt signaling pathway , familial adenomatous polyposis , cancer research , adenocarcinoma , beta catenin , mutation , exon , kras , microsatellite instability , colorectal cancer , microbiology and biotechnology , cancer , gene , genetics , microsatellite , allele
Abstract Small intestinal adenocarcinoma is rare and its molecular pathogenesis is incompletely understood. Stabilization of β‐catenin, a mediator of wnt/wingless signalling, can be detected in 50% of sporadic carcinomas but, in contrast to colorectal cancer, this finding can not be explained by the inactivation of adenomatous polyposis coli (APC). In order to elucidate the molecular background of β‐catenin stabilization in small intestinal adenocarcinoma, we investigated 20 non‐familial adenomatous polyposis coli (FAP)‐associated tumours, including five microsatellite‐unstable carcinomas for β‐catenin alterations, by immunohistochemistry, western blot analysis and sequence analysis on the RNA and DNA levels. Nuclear accumulation of β‐catenin was found in 50% of carcinomas. In 30%, nuclear stabilization was restricted to tumour cells at the invasion front, while 20% of tumours displayed intense homogeneous nuclear stabilization throughout all areas. Large deletions and insertions in the β‐catenin gene ( CTNNB1 ) resulting in a partial or complete in‐frame loss of exons 3 and 4 on the RNA‐transcript level were found in the latter, exclusively microsatellite‐stable carcinomas. The mutations resulted in the stabilization of aberrant β‐catenin lacking large parts of N‐terminal protein domains. No point mutations in CTNNB1 were observed. Our data show that large intragenic CTNNB1 mutations stabilize β‐catenin in small intestinal adenocarcinomas and influence the subcellular distribution of the protein. In contrast to colon carcinomas, neither APC nor CTNNB1 point mutations seem to play a significant role in carcinogenesis, indicating divergent mechanisms of wnt/wingless control in the small and the large intestine. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.