SDHC promoter methylation, a novel pathogenic mechanism in parasympathetic paragangliomas.

SDHC promoter methylation, a novel pathogenic mechanism in parasympathetic paragangliomas.

J Clin Endocrinol Metab. 2017 Nov 03;:

Authors: Bernardo-Castiñeira C, Valdés N, Sierra MI, Sáenz-de-Santa-María I, Bayón GF, Perez RF, Fernández AF, Fraga MF, Astudillo A, Menéndez R, Fernández B, Del Olmo M, Suarez C, Chiara MD

Abstract
Context: Germline mutations in the succinate dehydrogenase A, B, C, and D genes (collectively, SDHx) predispose to the development of paragangliomas (PGLs) arising at the parasympathetic or sympathetic neuroendocrine systems. SDHx mutations cause absence of tumoral immunostaining for SDHB. However, negative SDHB-immunostaining has also been found in a subset of PGLs that lack SDHx mutations.
Settings: Here, we report the comprehensive molecular characterization of one such a tumor of parasympathetic origin compared with healthy paraganglia and other PGLs with or without SDHx mutations.
Results: Integration of multi-platform data revealed somatic SDHC methylation and loss of the 1q23.3 region containing the SDHC gene. This correlated with decreased SDHC mRNA and protein levels. Furthermore, another genetic event found affected the VHL gene which showed decreased DNA copy number, associated with low VHL mRNA levels, and absence of VHL protein detected by immunohistochemistry. Additionally, the tumor displayed a pseudohypoxic phenotype consisting in over-expression of the hypoxia-inducible factor (HIF-1α) and miR-210, and down-regulation of the iron-sulfur cluster assembly enzyme (ISCU) involved in SDHB maturation. This profile resembles that of SDHx- or VHL-mutated PGLs but not of PGLs with decreased VHL-copy number, pointing to SDHC rather than VHL as the pathogenic driver.
Conclusions: Collectively, these findings demonstrate the potential importance of both, the SDHC epigenomic event and the activation of the HIF-1α/miR-210/ISCU axis in the pathogenesis of SDHx-wild type/SDHB negative PGLs. Moreover, this is the first case of a sporadic parasympathetic PGL that carries silencing of SDHC, fulfilling the two-hit Knudson's model for tumorigenesis.

PMID: 29126304 [PubMed - as supplied by publisher]

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