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A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours

Oncogene volume 24, pages 5344–5354 (2005)Cite this article

Abstract

Sensitivity to transforming growth factor-β is impaired in thyroid tumours. Similar to Mad – Mother Against Decapentaplegic-(Smad)4 is frequently altered in cancers, but its involvement in this system is unknown. We analysed 56 thyroid tumours of various histotypes for Smad4 mutations by PCR-SSCP and sequencing, linking them to Smad4 reactivity as examined by immunohistochemistry (IHC), and 29 of them also for abnormalities in RNA expression due to alternative splicing. In all, 15/56 cases (27%), both benign and malignant lesions, harbour alterations of Smad4 coding sequence. We found several novel intragenic mutations (13 missense, two silent, one frameshift and one large insertion-deletion), with high incidence in the linker region. A subset of mutated tumours failed to express Smad4 protein by IHC. We have also detected four alternatively spliced tumour-associated Smad4 isoforms, lacking portions of the linker region, and three more due to unreported internal exon–exon rearrangements. Smad4 is both frequently mutated and deregulated by aberrant splicing in thyroid tumours and these alterations may contribute as an early event to thyroid tumorigenesis.

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Acknowledgements

We thank Mr D Di Gianvito for excellent technical assistance with IHC and Mr V Pasceri (CEMAMIF) for exquisite art and graphics support in the figures. DL thanks Dr A Ranieri for scientific discussion. We acknowledge financial support from AIRC, MURST Project ‘Giovani Ricercatori’ 2001, CEA grant to the Ageing Research Center of the ‘G D'Annunzio’ University Foundation and CNR Strategic Project ‘ONCOLOGY’.

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Authors and Affiliations

  1. Department of Experimental Medicine and Pathology, I° Faculty of Medicine, University of Rome ‘La Sapienza’, V.le Regina Elena, 324, Rome, 00161, Italy

    Davide Lazzereschi, Francesco Nardi, Alessandra Turco, Laura Ottini, Alberto Gulino & Anna Coppa

  2. Department of Oncology and Neurosciences, Faculty of Medicine, University ‘G. D'Annunzio’ and Ageing Research Center, ‘G. D'Annunzio’ University Foundation, Chieti, 66013, Italy

    Cristina D'Amico & Renato Mariani-Costantini

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  1. Davide Lazzereschi
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  2. Francesco Nardi
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  3. Alessandra Turco
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Correspondence to Davide Lazzereschi.

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This work is dedicated to the memory of Professor Giulia Colletta, whom we miss dearly

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Lazzereschi, D., Nardi, F., Turco, A. et al. A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours. Oncogene 24, 5344–5354 (2005). https://doi.org/10.1038/sj.onc.1208603

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