Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.

Eur J Hum Genet 2008 Jan 1;16(1):79-88. Epub 2007 Aug 1.

Department of Genetics, Biology and Biochemistry, University of Torino, Turin, Italy.

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.ejhg.5201904DOI Listing
January 2008
20 Reads

Publication Analysis

Top Keywords

germline mutations
12
mutations genes
12
subunits sdhb
8
succinate dehydrogenase
8
sdhc sdhd
8
caused germline
8
gists caused
8
sdhb sdhc
8
respond sti571
8
gists
6
genes
5
associated paragangliomas
4
paragangliomas condition
4
lesions associated
4
patients gists
4
gists lesions
4
condition familial
4
transmitted autosomal-dominant
4
investigated patients
4
patients dyad
4

References

(Supplied by CrossRef)

BP Rubin et al.
Histopathology 2006

JA Carney et al.
Am J Med Genet 2002

O Daum et al.
Klinicka Onkologie 2006

L Amar et al.
J Clin Oncol 2005

FM Brouwers et al.
J Clin Endocrinol Metab 2006

F Schiavi et al.
JAMA 2005

M Bolland et al.
ANZ J Surg 2006

HP Neumann et al.
JAMA 2004

S Hirota et al.
Science 1998

A Chompret et al.
Gastroenterology 2004

Similar Publications