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

Davide Lazzereschi, Francesco Nardi, Alessandra Turco, Laura Ottini, Cristina D'Amico, Renato Mariani-Costantini, Alberto Gulino, Anna Coppa

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5344-5354
Number of pages11
JournalOncogene
Volume24
Issue number34
DOIs
Publication statusPublished - Aug 11 2005

Fingerprint

Thyroid Gland
Mutation
Neoplasms
Exons
Smad4 Protein
Immunohistochemistry
Single-Stranded Conformational Polymorphism
Alternative Splicing
Transforming Growth Factors
Missense Mutation
Protein Isoforms
Carcinogenesis
RNA
Polymerase Chain Reaction
Incidence

Keywords

  • Abnormal splicing
  • Molecular pathology
  • Smad4
  • Somatic mutations
  • TGF-β signalling
  • Thyroid tumours

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Lazzereschi, D., Nardi, F., Turco, A., Ottini, L., D'Amico, C., Mariani-Costantini, R., ... Coppa, A. (2005). A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours. Oncogene, 24(34), 5344-5354. https://doi.org/10.1038/sj.onc.1208603

A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours. / Lazzereschi, Davide; Nardi, Francesco; Turco, Alessandra; Ottini, Laura; D'Amico, Cristina; Mariani-Costantini, Renato; Gulino, Alberto; Coppa, Anna.

In: Oncogene, Vol. 24, No. 34, 11.08.2005, p. 5344-5354.

Research output: Contribution to journalArticle

Lazzereschi, D, Nardi, F, Turco, A, Ottini, L, D'Amico, C, Mariani-Costantini, R, Gulino, A & Coppa, A 2005, 'A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours', Oncogene, vol. 24, no. 34, pp. 5344-5354. https://doi.org/10.1038/sj.onc.1208603
Lazzereschi D, Nardi F, Turco A, Ottini L, D'Amico C, Mariani-Costantini R et al. A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours. Oncogene. 2005 Aug 11;24(34):5344-5354. https://doi.org/10.1038/sj.onc.1208603
Lazzereschi, Davide ; Nardi, Francesco ; Turco, Alessandra ; Ottini, Laura ; D'Amico, Cristina ; Mariani-Costantini, Renato ; Gulino, Alberto ; Coppa, Anna. / A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours. In: Oncogene. 2005 ; Vol. 24, No. 34. pp. 5344-5354.
@article{96295082e4124d8499945d6eb91f1018,
title = "A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours",
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.",
keywords = "Abnormal splicing, Molecular pathology, Smad4, Somatic mutations, TGF-β signalling, Thyroid tumours",
author = "Davide Lazzereschi and Francesco Nardi and Alessandra Turco and Laura Ottini and Cristina D'Amico and Renato Mariani-Costantini and Alberto Gulino and Anna Coppa",
year = "2005",
month = "8",
day = "11",
doi = "10.1038/sj.onc.1208603",
language = "English",
volume = "24",
pages = "5344--5354",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "34",

}

TY - JOUR

T1 - A complex pattern of mutations and abnormal splicing of Smad4 is present in thyroid tumours

AU - Lazzereschi, Davide

AU - Nardi, Francesco

AU - Turco, Alessandra

AU - Ottini, Laura

AU - D'Amico, Cristina

AU - Mariani-Costantini, Renato

AU - Gulino, Alberto

AU - Coppa, Anna

PY - 2005/8/11

Y1 - 2005/8/11

N2 - 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.

AB - 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.

KW - Abnormal splicing

KW - Molecular pathology

KW - Smad4

KW - Somatic mutations

KW - TGF-β signalling

KW - Thyroid tumours

UR - http://www.scopus.com/inward/record.url?scp=24044432265&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24044432265&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1208603

DO - 10.1038/sj.onc.1208603

M3 - Article

C2 - 15940269

AN - SCOPUS:24044432265

VL - 24

SP - 5344

EP - 5354

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 34

ER -