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Eur J Hum Genet. 2014 Jan;22(1):32-9. doi: 10.1038/ejhg.2013.80. Epub 2013 Apr 24.

Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST.

Author information

1
Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
2
8216;Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.
3
Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
4
Biocomputing Group, Department of Biology, University of Bologna, Bologna, Italy.
5
Section of Pathologic Anatomy and Division of Oncology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy.
6
Laboratorio di Patologia Molecolare Oncologica e dei Trapianti-Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
7
Oncologia Medica 1, Istituto Oncologico Veneto IOV I.R.C.C.S., Padova, Italy.
8
1] Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy [2] 'Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.

Abstract

Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. In this study, we simultaneously sequenced the genome of all subunits, SDHA, SDHB, SDHC, and SDHD in a larger series of KIT/PDGFRA wild-type GIST in order to evaluate the frequency of the mutations and explore their biological role. SDHA, SDHB, SDHC, and SDHD were sequenced on the available samples obtained from 34 KIT/PDGFRA wild-type GISTs. Of these, in 10 cases, both tumor and peripheral blood (PB) were available, in 19 cases only tumor, and in 5 cases only PB. Overall, 9 of the 34 patients with KIT/PDGFRA wild-type GIST carried mutations in one of the four subunits of the SDH complex (six patients in SDHA, two in SDHB, one in SDHC). WB and immunohistochemistry analysis showed that patients with KIT/PDGFRA wild-type GIST who harbored SDHA mutations exhibited a significant downregulation of both SDHA and SDHB protein expression, with respect to the other GIST lacking SDH mutations and to KIT/PDGFRA-mutated GIST. Clinically, four out of six patients with SDHA mutations presented with metastatic disease at diagnosis with a very slow, indolent course. Patients with KIT/PDGFRA wild-type GIST may harbor germline and/or de novo mutations of SDH complex with prevalence for mutations within SDHA, which is associated with a downregulation of SDHA and SDHB protein expression. The presence of germline mutations may suggest that these patients should be followed up for the risk of development of other cancers.

PMID:
23612575
PMCID:
PMC3865408
DOI:
10.1038/ejhg.2013.80
[Indexed for MEDLINE]
Free PMC Article

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