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.

Classification of gastrointestinal stromal tumor syndromes

“…Killian et al then confirmed these results, performing genomewide DNA methylation profiling and demonstrating that six of the 15 Carney triad patients had SDHC epimutation (Haller et al 2014, Killian et al 2014. Finally, very recently, SDHx mutations were found in patients with Carney triad, suggesting that the various SDH-deficient syndromes overlap significantly (Boikos et al 2016b).…”

A bittersweet symphony

“…While the findings described herein by Haller et al (2014) are the first to definitively link SDHC genetic dysregulation to tumorigenesis in Carney triad, earlier work from the Stratakis group had suggested that SDHC might have a role to play. Matyakhina et al (2007) demonstrated that among 41 tumors in 37 cases of Carney triad, the most frequent recurrent genetic abnormality was a large-scale copy number loss that included the locus for SDHC (chromosome 1q21-q23.3).…”

“…This epigenetic silencing profile of SDHB, along with SDHB copy number changes and loss of SDHB staining in Carney triad tumors implies that SDHx-related abnormalities might be somewhat more generalized than SDHC alone (Matyakhina et al 2007, Haller et al 2014. Study of more Carney triad tumors will help to define the relative variability or specificity of hypermethylation patterns in SDHC and SDHB.…”

“…For instance, epigenetic alterations are well established as playing an important role in both syndromic and sporadic endocrine cancers (RodriguezRodero et al 2014). This issue of Endocrine-Related Cancer reports results of a new study that demonstrates that specific and preferential hypermethylation of one SDH subunit gene (SDHC) is a crucial pathophysiological event in Carney triad (Haller et al 2014). This study led by groups at the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Friedrich-Alexander University Erlangen-Nuremberg, Germany, demonstrates that hypermethylation of the SDHC promoter region is an abnormality that is specific to Carney triad tumors when compared with similar tumors that occurred outside of the setting of Carney triad.…”

DIAGNOSIS of ENDOCRINE DISEASE: SDHx mutations: beyond pheochromocytomas and paragangliomas

“…Nonetheless, the GISTs from Carney triad display loss of immunoreactivity for SDHB (39). This finding can be explained by SDHx somatic losses or by epigenetic silencing of SDHC promoter (40). SDH-deficient GISTs account for 5-7.5% of all GISTs.…”