Aberrant DNA hypermethylation of SDHC: A novel mechanism of tumor development in Carney Triad. F. Faucz1, F. Haller2, E. A. Moskalev2, S. Batthelmeb2, S. Wiemann3, M. Bieg4, G. Assie5,6, J. Bertherat5,6, I.-M. Schaefer7,12, C. Otto8, E. Rattenberry9, E. R. Maher9,10, P. Strobel7, M. Werner8, J. A. Carney11, A. Hartmann2, A. Agamy2, C. A. Stratakis1 1) Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA; 2) Institute of Pathology, University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; 3) Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany; 4) Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany; 5) Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 6) Department of Endocrinology, Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France; 7) Institute of Pathology, University Hospital, Georg-August University, Göttingen, Germany; 8) Institute of Pathology, University Hospital, Albert-Ludwigs University Freiburg, Freiburg, Germany; 9) Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; 10) Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK; 11) Laboratory Medicine and Pathology, Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA; 12) Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs) and pulmonary chondromas in a patient. The disease has a striking predilection for young females, for reasons that remain unknown. In contrast to Carney-Stratakis Syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase complex (SDH) subunits A, B, C or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. Given the shared loss of SDHB protein in tumors among all three syndromes, we hypothesized epigenetic silencing of SDH genes as an alternate mechanism in tumors occurring in CT patients. For the current study we performed broad, high-resolution and quantitative assessment of DNA methylation to evaluate CpG islands pattern in the proximity of transcriptional start sites of all four genes encoding the SDH subunits in tumors from four CT patients who did not have any SDH coding sequence abnormalities. The DNA methylation patterns were compared to tumors from a patient with CSS, a patient with PGL1 as well as sporadic GISTs harboring mutations in the KIT receptor. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of the SDHC in all tumors from the CT patients, while virtually no methylation was detectable in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. mRNA expression of all four SDH subunits A, B, C and D was determined by qPCR, and a significant downregulation of SDHC on mRNA level in the CT tumors was observed what was in contrast to a virtually equal expression of all four SDH subunits in the other tumor samples. Both SDHB and SDHC subunits were absent at the protein level in the tumors from the CT patients. Collectively, these data demonstrate that DNA methylation of the SDHC gene locus is a recurrent and specific event in tumors of CT patients, and suggests SDHC downregulation by epigenetic inactivation as a plausible tumor-initiating event.
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