Germline APC mutation on the β-catenin binding site is associated with a decreased apoptotic level in colorectal adenomas

Tiziana Venesio, Antonella Balsamo, Antonella Scordamaglia, Marta Bertolaso, Arrigo Arrigoni, Tatiana Sprujevnik, Francesco P. Rossini, Mauro Risio

Research output: Contribution to journalArticlepeer-review

Abstract

Germline mutations in APC tumor suppressor gene are responsible for familial adenomatous polyposis (FAP). A major role of these genetic changes is the constitutive activation of β-catenin-Tcf-4 mediated transcription of nuclear target genes, but other cellular functions can be misregulated. To assess how different APC mutations can drive the early steps of colonic tumorigenesis, we studied the effect of 10 different germline-truncating alterations on the phenotype of the corresponding adenomas. A significant reduction of apoptosis, uncoupled with an increased c-myc and cyclin-D1 expression, was seen with a frameshift mutation on codon 1383, in the 20-aa repeats of the β-catenin degradation domain, independent of a somatic alteration on the wild-type allele. The decreased apoptotic level was associated with a higher incidence of cancerization. No other APC mutation was linked with a similar effect, even in presence of a somatic allelic loss. These findings suggest that mutations in critical sites of the β-catenin degradation domain of APC gene can convey a selective advantage to the colonic neoplastic clones by altering the apoptotic surveillance rather than enhancing the β-catenin-Tcf-4 transcription of growth-promoting genes.

Original languageEnglish
Pages (from-to)57-65
Number of pages9
JournalModern Pathology
Volume16
Issue number1
DOIs
Publication statusPublished - Jan 1 2003

Keywords

  • β-Catenin
  • APC
  • Apoptosis
  • Colorectal adenomas
  • Familial adenomatous polyposis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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