Familial Cancer

, Volume 9, Issue 3, pp 395–400 | Cite as

A distinct mutation on the alternative splice site of APC exon 9 results in attenuated familial adenomatous polyposis phenotype

  • Florentia Fostira
  • Drakoulis Yannoukakos


A subset of APC mutation carriers shows a milder familial adenomatous polyposis phenotype (attenuated FAP) developing smaller number of polyps and colorectal cancer at an older age. It seems that a different mechanism to carcinogenesis is initiated according to the initial site of the germline mutation. The APC gene of a female patient with AFAP phenotypic features was analysed. A novel mutation located on the alternatively splice site of exon 9 was identified. This is the first reported mutation in the specific site. Transcripts characterization revealed disruption of splicing occurring within exon 9, resulting in the expression of a shorter mRNA transcript, which surprisingly does not affect the ratio between the two wild type transcripts, as well as the production of wild type short isoform by the mutant allele. The short wild type isoform, produced by the mutant allele, needs to be inactivated, on top of the wild type allele, for colorectal cancer to develop. These observations enhance the ‘three hit hypothesis’ and indicate that a distinct mechanism for the adenoma to carcinoma sequence should be followed, for truncated mutations taking place on the borderline of the alternatively spliced exon 9 of the APC gene, as well.


Familial colorectal cancer FAP APC Exon 9 Alternative splicing 



This work is funded by 75% from the European Union—European Social Fund (E.S.F) and by 25% from the Greek Ministry of Development—General Secretary for Research & Technology (GSRT) and the private sector in the frame of Measure 8.3 of the Operational Program—Competitiveness—3rd Framework program (PENED03ΕΔ562). We would also like to thank Dr Ioannis Robotis for providing fresh polyp samples essential to carry out the tissue experiments.


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© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Molecular Diagnostics Laboratory, I/R-RPNational Center for Scientific Research “Demokritos”AthensGreece

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