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Constitutional high expression of an APC mRNA isoform in a subset of attenuated familial adenomatous polyposis patients

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Abstract

Familial adenomatous polyposis is an inherited condition associated with hundreds to thousands of colorectal adenomas conferring a very high risk of cancer at a young age. In addition to “classical” form, there is also an attenuated polyposis, with fewer than 100 polyps and a delayed age of cancer onset. Both classical and attenuated polyposis are characterized by a relevant phenotypic heterogeneity. The disease has been linked to constitutive mutations of either APC tumor suppressor gene, or less frequently, MYH base-excision repair gene. However, the genetic cause remains undetected in up to 70–80% of patients with the attenuated form. This analysis was performed on 26 polyposis patients with the attenuated phenotype. All patients had formerly proven to be negative for APC truncating mutations that typically represent the majority of APC gene alterations. We evaluated the APC mRNA constitutional level by real-time quantitative reverse transcription polymerase chain reaction (PCR). Eleven patients (42%) showed an anomalous APC transcription level. One patient with reduced mRNA was a carrier of a whole APC gene deletion. In seven out of the ten remaining cases, we found the increased expression of an APC mRNA isoform resulting from exon 10/15 connection and giving rise to a stable truncated peptide. Mutations neither in the invariant splice sites nor in the known transcription regulatory signals were found. Our results support the notion that in attenuated polyposis patients, a detailed investigation of APC transcription can allow detection of rare alterations. Although functional data are required, the isoform we observed might have some pathogenic role, accounting for the heterogeneous phenotype that characterizes the polyposis syndrome.

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Acknowledgements

We thank Prof. Michele De Bortoli for the advice and helpful discussions and Mrs. Claudia Chiabert for technical assistance.

This study was supported by the Italian Association for Cancer Research (AIRC)—Regional Project 2005 and by PRIN-MIUR 2004.

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Authors and Affiliations

  1. Unit of Pathology, Institute for Cancer Research and Treatment—IRCC, Strada Provinciale 142, 10060, Candiolo, Torino, Italy

    Tiziana Venesio, Antonella Balsamo & Mauro Risio

  2. Oncological Science Department, Institute for Cancer Research and Treatment-IRCC, Strada Provinciale 142, 10060, Candiolo, Torino, Italy

    Christian Sfiligoi & Luca Fuso

  3. Department of Genetics and Microbiology, University of Pavia, Pavia, Italy

    Sara Molatore & Guglielmina Nadia Ranzani

Authors
  1. Tiziana Venesio
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  2. Antonella Balsamo
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  3. Christian Sfiligoi
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  4. Luca Fuso
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  5. Sara Molatore
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  6. Guglielmina Nadia Ranzani
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  7. Mauro Risio
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Correspondence to Tiziana Venesio.

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Venesio, T., Balsamo, A., Sfiligoi, C. et al. Constitutional high expression of an APC mRNA isoform in a subset of attenuated familial adenomatous polyposis patients. J Mol Med 85, 305–312 (2007). https://doi.org/10.1007/s00109-006-0127-4

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  • DOI: https://doi.org/10.1007/s00109-006-0127-4

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