Endocrine Abstracts
BioScientifica, Endocrine-Related Cancer, 4(21), p. 567-577, 2014
DOI: 10.1530/erc-14-0254
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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. 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. For the current study we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of the SDH subunit C (SDHC) in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the succinate dehydrogenase complex as a plausible alternate mechanism of tumorigenesis in CT.