APC Haploinsufficiency, but Not CTNNB1 or CDH1 Gene Mutations, Accounts for a Fraction of Familial Adenomatous Polyposis Patients Without APC Truncating Mutations

Tiziana Venesio, Antonella Balsamo, Marco Rondo-Spaudo, Liliana Varesco, Mauro Risio, Guglielmina Nadia Ranzani

Research output: Contribution to journalArticle

Abstract

Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of hundreds to thousands of colorectal adenomatous polyps. In addition to the classic form, there is also attenuated polyposis (attenuated adenomatous polyposis coli; AAPC), which is characterized by a milder phenotype. FAP/AAPC is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Very recently, germline mutations in the base-excision repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas in a subset of patients. APC pathogenic alterations are mostly (>95%) represented by frameshift or nonsense mutations leading to the synthesis of a truncated protein. We identified 20 APC truncating mutation carriers out of 30 FAP/AAPC patients from different Italian kindreds. In the remaining 10 patients, we searched for alterations other than truncating mutations by enzymatic mutation detection, real-time quantitative RT-PCR, and genotyping of polymorphic markers encompassing the APC locus. Moreover, to assess whether mutations of genes interacting with APC can substitute or act in association with APC alterations, we sequenced both CTNNB1 (β-catenin) and CDH1 (E-cadherin) genes. No CTNNB1 or CDH1 mutations were found. On the contrary, four patients showed a reduced APC gene expression compared with healthy subjects. In three of the four cases, genotyping results were compatible with a constitutive allelic deletion. In one case this conclusion was confirmed by haplotype segregation analysis. Our results support the notion that FAP/AAPC can result from APC constitutive haploinsufficiency, with gene deletion being a possible cause of reduced gene expression.

Original languageEnglish
Pages (from-to)1859-1866
Number of pages8
JournalLaboratory Investigation
Volume83
Issue number12
DOIs
Publication statusPublished - Dec 2003

Fingerprint

Haploinsufficiency
Adenomatous Polyposis Coli
Mutation
Genes
APC Genes
Germ-Line Mutation
Adenomatous Polyps
Gene Expression
Catenins
Frameshift Mutation
Nonsense Codon
Gene Deletion
Cadherins
DNA Repair
Adenoma
Haplotypes
Real-Time Polymerase Chain Reaction
Healthy Volunteers
Phenotype

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

APC Haploinsufficiency, but Not CTNNB1 or CDH1 Gene Mutations, Accounts for a Fraction of Familial Adenomatous Polyposis Patients Without APC Truncating Mutations. / Venesio, Tiziana; Balsamo, Antonella; Rondo-Spaudo, Marco; Varesco, Liliana; Risio, Mauro; Ranzani, Guglielmina Nadia.

In: Laboratory Investigation, Vol. 83, No. 12, 12.2003, p. 1859-1866.

Research output: Contribution to journalArticle

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abstract = "Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of hundreds to thousands of colorectal adenomatous polyps. In addition to the classic form, there is also attenuated polyposis (attenuated adenomatous polyposis coli; AAPC), which is characterized by a milder phenotype. FAP/AAPC is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Very recently, germline mutations in the base-excision repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas in a subset of patients. APC pathogenic alterations are mostly (>95{\%}) represented by frameshift or nonsense mutations leading to the synthesis of a truncated protein. We identified 20 APC truncating mutation carriers out of 30 FAP/AAPC patients from different Italian kindreds. In the remaining 10 patients, we searched for alterations other than truncating mutations by enzymatic mutation detection, real-time quantitative RT-PCR, and genotyping of polymorphic markers encompassing the APC locus. Moreover, to assess whether mutations of genes interacting with APC can substitute or act in association with APC alterations, we sequenced both CTNNB1 (β-catenin) and CDH1 (E-cadherin) genes. No CTNNB1 or CDH1 mutations were found. On the contrary, four patients showed a reduced APC gene expression compared with healthy subjects. In three of the four cases, genotyping results were compatible with a constitutive allelic deletion. In one case this conclusion was confirmed by haplotype segregation analysis. Our results support the notion that FAP/AAPC can result from APC constitutive haploinsufficiency, with gene deletion being a possible cause of reduced gene expression.",
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