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APC rearrangements in familial adenomatous polyposis: heterogeneity of deletion lengths and breakpoint sequences underlies similar phenotypes

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Abstract

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome leading to the development of multiple intestinal polyps and colorectal cancer. FAP is associated with germline defects of APC tumor suppressor gene; although truncating mutations account for the majority of cases, large APC deletions represent a common disease-causing defect. While a number of intragenic deletions have been well-characterized, sequencing data of breakpoints involved in large APC rearrangements are extremely scanty. We characterized six deletions identified by multiplex ligation-dependent probe amplification (three intragenic and three larger deletions encompassing the APC locus): in each case, we precisely mapped the breakpoints by array-comparative genomic hybridization and/or long-range PCR followed by sequencing. All rearrangements were novel and no rearrangements proved to be recurrent or clustered. The three intragenic deletions involved exons 4, 9 and 14, respectively; larger deletions (30,444, 265,471 and 921,295 bp in length) involved APC as well as adjacent genes. Nine out of 12 breakpoints fell within repetitive elements (5 Alu, 2 LINE, 1 Tigger and 1 MIR), while the remaining 3 fell within unique sequences. In five out of six patients, non-allelic homologous recombination or non-homologous end joining appear as the most likely mechanisms behind APC rearrangements. Although a certain variability of clinical features was detectable both between and within families with deletions, all deletion carriers were classifiable as FAP patients showing colonic and extracolonic manifestations that belong to the spectrum of the syndrome. Therefore, different sized deletions, variable breakpoint localizations and haploinsufficiency for other genes besides APC, resulted in the same FAP clinical phenotype.

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Acknowledgments

The Unit of Hereditary Cancer (VG, LV) was supported by projects of “Fondi 5 per mille” to IRCCS AOU San Martino-IST, Genoa.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Author notes

  1. Marialuisa Quadri

    Present address: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands

Authors and Affiliations

  1. Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100, Pavia, Italy

    Marialuisa Quadri, Monica Marabelli & Guglielmina N. Ranzani

  2. Biotechnology Research Laboratory, Foundation IRCCS, Policlinico San Matteo, Pavia, Italy

    Annalisa Vetro

  3. Unit of Hereditary Cancer, IRCCS AOU San Martino-IST, Genoa, Italy

    Viviana Gismondi & Liliana Varesco

  4. Unit of Hereditary Digestive Tract Tumors, Department of Preventive and Predictive Medicine, Foundation IRCCS-INT, Milan, Italy

    Lucio Bertario & Paola Sala

  5. Department of Molecular Medicine, University of Pavia, Pavia, Italy

    Orsetta Zuffardi

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  1. Marialuisa Quadri
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  2. Annalisa Vetro
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  9. Guglielmina N. Ranzani
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Corresponding author

Correspondence to Guglielmina N. Ranzani.

Additional information

Marialuisa Quadri and Annalisa Vetro have contributed equally to this work.

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Quadri, M., Vetro, A., Gismondi, V. et al. APC rearrangements in familial adenomatous polyposis: heterogeneity of deletion lengths and breakpoint sequences underlies similar phenotypes. Familial Cancer 14, 41–49 (2015). https://doi.org/10.1007/s10689-014-9750-3

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  • DOI: https://doi.org/10.1007/s10689-014-9750-3

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