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Epigenetic Mutation of the Succinate Dehydrogenase C Promoter in a Patient With Two Paragangliomas
Susan Richter1, Barbara Klink1, Brit Nacke1
1Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
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:
A 33-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.
Insights
Epigenetic silencing of the SDHC gene through promoter methylation can cause paragangliomas (PGLs). This finding highlights the importance of considering epigenetic alterations in PGL diagnosis.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Succinate dehydrogenase (SDH) complex mutations are known drivers of pheochromocytoma/paraganglioma (PPGL) and gastrointestinal stromal tumor (GIST) development.
- Epigenetic inactivation of SDHC, a component of the SDH complex, has been recently identified in GISTs and PPGLs associated with Carney triad syndrome.
Observation:
- A patient presented with two abdominal paragangliomas (PGLs) and an adrenocortical adenoma, exhibiting high succinate:fumarate ratios suggestive of SDHx mutations.
- Genetic analysis revealed no mutations in known PPGL susceptibility genes, but SDHC promoter methylation was detected in both PGLs.
- This methylation correlated with reduced SDHC expression and a hypermethylated epigenomic signature, suggesting epigenetic silencing.
Findings:
- SDHC promoter methylation was identified as a causative mechanism for PGL development in this patient.
- Evidence of postzygotic somatic mosaicism for SDHC promoter methylation was observed, with low-level methylation present in the adenoma but not normal tissues.
Implications:
- This study underscores that SDHC promoter methylation can lead to PGLs via SDHC inactivation.
- The findings emphasize the critical role of evaluating epigenetic modifications and functional readouts in the genetic assessment of PPGL patients, extending beyond GISTs and Carney triad.
