Germline APC mutation on the beta-catenin binding site is associated with a decreased apoptotic level in colorectal adenomas.
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 beta-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 beta-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 beta-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 beta-catenin-Tcf-4 transcription of growth-promoting genes.
Venesio
Tiziana
T
Unit of Pathology, Institute for Cancer Research and Treatment (IRCC), Candiolo-Torino, Italy.
Balsamo
Antonella
A
Scordamaglia
Antonella
A
Bertolaso
Marta
M
Arrigoni
Arrigo
A
Sprujevnik
Tatiana
T
Rossini
Francesco P
FP
Risio
Mauro
M
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1