Sensitivity to transforming growth factor-beta 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.

A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours / Lazzereschi, Davide; Nardi, Francesco; Alessandra, Turco; Ottini, Laura; Cristina, D'Amico; Renato Mariani, Costantini; Gulino, Alberto; Coppa, Anna. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 24:34(2005), pp. 5344-5354. [10.1038/sj.onc.1208603]

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

LAZZERESCHI, DAVIDE;NARDI, Francesco;OTTINI, LAURA;GULINO, Alberto;COPPA, Anna
2005

Abstract

Sensitivity to transforming growth factor-beta 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.
abnormal splicing; molecular pathology; smad4; somatic mutations; tgf-beta signalling; tgf-β signalling; thyroid tumours
01 Pubblicazione su rivista::01a Articolo in rivista
A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours / Lazzereschi, Davide; Nardi, Francesco; Alessandra, Turco; Ottini, Laura; Cristina, D'Amico; Renato Mariani, Costantini; Gulino, Alberto; Coppa, Anna. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 24:34(2005), pp. 5344-5354. [10.1038/sj.onc.1208603]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/231719
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