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Genetics of Carney Triad: Recurrent Losses at Chromosome 1 but Lack of Germline Mutations in Genes Associated with Paragangliomas and Gastrointestinal Stromal Tumors

Section on Endocrinology and Genetics (L.M., T.A.B., S.G.S., S.B., M.M., A.D., E.P., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Cytogenetic and Microscopy Core, National Human Genome Research Institute (A.D., E.P.), National Institutes of Health, Bethesda, Maryland 20892; Department of Molecular Genetics (S.R.M., C.E.), The Ohio State University, Columbus, Ohio 43210; Department of Genetics, Biology and Biochemistry (B.P.), University of Turin, 10129 Turin, Italy; Departments of Gastroenterology and Gastroenteropathology (S.C., B.G., L.F.), University Clinic of the Georg August Göttingen University, Göttingen 37099, Germany; Departments of Pathology and Hematopathology Unit and Internal Medicine (E.C., M.C.C.), Hospital Clinic, University of Barcelona, Villarroel, 17008036 Barcelona, Spain; Service d’ Endocrinologie, Diabétologie et du Métabolisme (F.G., R.C.G.), Centre Hospitalier Universitaire Vaudois-CHUV, CH-1011 Lausanne, Switzerland; Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Center, Cleveland Clinic Foundation (G.A., C.E.), Cleveland, Ohio 44195; Institut National de la Santé et de la Recherche Médicale U567 (G.A.), Institut Cochin, Département d’Endocrinologie, F-75014 Paris, France; Department of Obstetrics, Gynecology, and Reproductive Sciences (B.E.B.), The University of Pittsburgh School of Medicine, Magee Women’s Research Institute, Pittsburgh, Pennsylvania 15213; and Department of Laboratory Medicine and Pathology (Emeritus member) (J.A.C.), Mayo Clinic and Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D(Med).Sc., Chief, Section on Endocrinology and Genetics (SEGEN) and Director, Pediatric Endocrinology Training Program, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892. E-mail: stratakc{at}mail.nih.gov.

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

Objective: Our objective was 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: Three males and 34 females with CT were studied retrospectively. We sequenced the stated genes and performed comparative genomic hybridization on a total of 41 tumors.

Results: No patient had coding sequence mutations of the investigated genes. Comparative genomic hybridization 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, and the average number of alterations in malignant tumors was higher compared with 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.

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