Large-scale N-terminal deletions but not point mutations stabilize beta-catenin in small bowel carcinomas, suggesting divergent molecular pathways of small and large intestinal carcinogenesis.
Small intestinal adenocarcinoma is rare and its molecular pathogenesis is incompletely understood. Stabilization of beta-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 beta-catenin stabilization in small intestinal adenocarcinoma, we investigated 20 non-familial adenomatous polyposis coli (FAP)-associated tumours, including five microsatellite-unstable carcinomas for beta-catenin alterations, by immunohistochemistry, western blot analysis and sequence analysis on the RNA and DNA levels. Nuclear accumulation of beta-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 beta-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 beta-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 beta-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.
Breuhahn
K
K
Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany.
Singh
S
S
Schirmacher
P
P
Bläker
H
H
D000230:Adenocarcinoma / Q000235:genetics*; D011125:Adenomatous Polyposis Coli; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D004379:Duodenal Neoplasms / Q000235:genetics; D005091:Exons; D005260:Female; D017491:Genes, APC; D006801:Humans; D007078:Ileal Neoplasms / Q000235:genetics; D015151:Immunoblotting; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics*; D007580:Jejunal Neoplasms / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D017423:Sequence Analysis, RNA; D017384:Sequence Deletion; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000032:analysis / Q000235:genetics*
C495270:CTNNB1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin