TY - JOUR
T1 - Epigenetic mutation of the succinate dehydrogenase c promoter in a patient with two paragangliomas
AU - Richter, Susan
AU - Klink, Barbara
AU - Nacke, Brit
AU - De Cubas, Aguirre A.
AU - Mangelis, Anastasios
AU - Rapizzi, Elena
AU - Meinhardt, Matthias
AU - Skondra, Christina
AU - Mannelli, Massimo
AU - Robledo, Mercedes
AU - Menschikowski, Mario
AU - Eisenhofer, Graeme
PY - 2016/2
Y1 - 2016/2
N2 - Context: Mutational inactivation of the succinate dehydrogenase (SDH) complex is a well-described cause of tumor development in pheochromocytomas/paragangliomas (PPGLs) and gastrointestinal stromal tumors (GISTs). Epigenetic inactivation of the SDHC gene is a more recently discovered phenomenon, which so far has only been described in GISTs and PPGLs from patients with Carney triad syndrome. Case Description:A33-year-old patient presented with two abdominal paragangliomas (PGLs) and an adrenocortical adenoma. Both PGLs showed high succinate:fumarate ratios indicative of SDHx mutations; however, no mutations in any of the known PPGL susceptibility genes were found in leucocyte or tumor DNA. We identified methylation of the SDHC promoter region in both PGLs, which coincided with decreased SDHC expression at mRNA and protein levels and a hypermethylated epigenomic signature (CpG island methylator phenotype). Low-level SDHC promoter methylation was also observed in the adenoma but not in normal adrenal tissue or blood, suggesting postzygotic somatic mosaicism for SDHC promoter methylation in the patient. Conclusions: This report provides evidence that SDHC promoter methylation can cause PGLs due to SDHC inactivation, emphasizing the importance of considering epigenetic changes and functional readouts in the genetic evaluation of patients not only with GISTs and Carney triad but also with PPGL.
AB - Context: Mutational inactivation of the succinate dehydrogenase (SDH) complex is a well-described cause of tumor development in pheochromocytomas/paragangliomas (PPGLs) and gastrointestinal stromal tumors (GISTs). Epigenetic inactivation of the SDHC gene is a more recently discovered phenomenon, which so far has only been described in GISTs and PPGLs from patients with Carney triad syndrome. Case Description:A33-year-old patient presented with two abdominal paragangliomas (PGLs) and an adrenocortical adenoma. Both PGLs showed high succinate:fumarate ratios indicative of SDHx mutations; however, no mutations in any of the known PPGL susceptibility genes were found in leucocyte or tumor DNA. We identified methylation of the SDHC promoter region in both PGLs, which coincided with decreased SDHC expression at mRNA and protein levels and a hypermethylated epigenomic signature (CpG island methylator phenotype). Low-level SDHC promoter methylation was also observed in the adenoma but not in normal adrenal tissue or blood, suggesting postzygotic somatic mosaicism for SDHC promoter methylation in the patient. Conclusions: This report provides evidence that SDHC promoter methylation can cause PGLs due to SDHC inactivation, emphasizing the importance of considering epigenetic changes and functional readouts in the genetic evaluation of patients not only with GISTs and Carney triad but also with PPGL.
UR - http://www.scopus.com/inward/record.url?scp=84959349359&partnerID=8YFLogxK
U2 - 10.1210/jc.2015-3856
DO - 10.1210/jc.2015-3856
M3 - Article
C2 - 26652933
AN - SCOPUS:84959349359
SN - 0021-972X
VL - 101
SP - 359
EP - 363
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 2
ER -