Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad.

Abstract:

: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 (SDH) complex 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 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 SDH complex as a plausible alternate mechanism of tumorigenesis in CT.

journal_name

Endocr Relat Cancer

journal_title

Endocrine-related cancer

authors

Haller F,Moskalev EA,Faucz FR,Barthelmeß S,Wiemann S,Bieg M,Assie G,Bertherat J,Schaefer IM,Otto C,Rattenberry E,Maher ER,Ströbel P,Werner M,Carney JA,Hartmann A,Stratakis CA,Agaimy A

doi

10.1530/ERC-14-0254

subject

Has Abstract

pub_date

2014-08-01 00:00:00

pages

567-77

issue

4

eissn

1351-0088

issn

1479-6821

pii

ERC-14-0254

journal_volume

21

pub_type

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