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This version published online on May 29, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-0797
A more recent version of this article appeared on August 1, 2007
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Submitted on April 9, 2007
Accepted on May 21, 2007

Genetics of Carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors

Ludmila Matyakhina, Thalia A. Bei, Sarah R. McWhinney, Barbara Pasini, Silke Cameron, Bastian Gunawan, Sotirios G. Stergiopoulos, Sosipatros Boikos, Michael Muchow, Amalia Dutra, Evegenia Pak, Elias Campo, Maria C. Cid, Fulgencio Gomez, Rolf C. Gaillard, Guillaume Assié, Laszlo Füzesi, Bora E. Baysal, Charis Eng, J. Aidan Carney, and Constantine A. Stratakis*

Section on Endocrinology & Genetics, DEB, NICHD, NIH, Bethesda, MD20892; and Department of Molecular Genetics, The Ohio State University, Columbus, OH43210, USA; University of Turin, Department of Genetics, Biology and Biochemistry, Turin, Italy; Departments of Gastroenterology and Gastroenteropathology, University Clinic of the Georg August Göttingen University, Göttingen 37099, Germany; Departments of Pathology and Hematopathology Unit and Internal Medicine, Hospital Clinic, University of Barcelona Villarroel 17008036 Barcelona, Spain; Service d' Endocrinologie, Diabétologie et du Métabolisme, Centre Hospitalier Universitaire Vaudois-CHUV, CH-1011 Lausanne, Switzerland; Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH44195, USA; INSERM U567, Institut Cochin, Département d'Endocrinologie, Paris, F-75014, France; Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Pittsburgh School of Medicine, Magee Women's Research Institute, Pittsburgh, PA, 15213; and Department of Laboratory Medicine and Pathology (Emeritus member), Mayo Clinic and Foundation, Rochester, MN55905, USA

* To whom correspondence should be addressed. E-mail: stratakc{at}mail.nih.gov.

Context: Carney triad (CT) describes the association of paragangliomas (PGLs) with gastric stromal tumors (GISTs) and pulmonary chondromas (PCH). Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD are found in PGLs, and gain-of-function mutations of c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) in GISTs.

Objective: To investigate the possibility that patients with CT and/or their tumors may harbor mutations of the SDHB, SDHC, SDHD, KIT, and PDGFRA genes and identify any other genetic alterations in CT tumors.

Design: 34 females and 3 males with CT were studied retrospectively. We sequenced the stated genes and performed comparative genomic hybridization (CGH) on a total of 41 tumors.

Results: No patient had coding sequence mutations of the investigated genes. CGH revealed a number of DNA copy number changes: losses dominated among benign lesions: there were an equal number of gains and losses in malignant lesions; the average number of alterations in malignant tumors was higher compared to benign lesions. The most frequent and greatest contiguous change was 1q12-q21 deletion, a region that harbors the SDHC gene. Another frequent change was loss of 1p. Allelic losses of 1p and 1q were confirmed by fluorescent in situ hybridization and loss-of-heterozygosity studies.

Conclusions: We conclude that CT is not due to SDH-inactivating or KIT- and PDGFRA-activating mutations. GISTs and PGLs in CT are associated with chromosome 1 and other changes that appear to participate in tumor progression and point to their common genetic cause.
Key words: Gastrointestinal stromal tumors • succinate dehydrogenase subunits A B C D • paraganglioma • tumor suppressor gene • genetics




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