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. 2024 Oct 1;130(19):3289-3296.
doi: 10.1002/cncr.35426. Epub 2024 Jun 14.

Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma

Anna Kaplinsky  1   2 , Reut Halperin  2   3 , Gadi Shlomai  2   4 , Amit Tirosh  2   3
Affiliations
Free article

Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma

Anna Kaplinsky et al. Cancer. .
Free article

Abstract

Introduction: Pheochromocytomas and paragangliomas (PPGLs) typically secrete catecholamines and their metabolites (metanephrines [MN] and normetanephrine [NMN]). Catecholamines are synthesized by several enzymes: phenylalanine hydroxylase (encoded by PAH), tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (DDC), dopamine β-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT). MN/NMN secretion varies between anatomical and molecular subgroups. The aim of this study was to assess the correlation between DNA methylation of catecholamine synthesis genes and MN/NMN secretion.

Methods: Gene promoter methylation of PAH, TH, AADC, DBH, and PNMT were extracted and calculated based on publicly available data. Comparisons and correlation analysis were performed between MN ± NMN (MN/NMN), NMN only, and neither/unknown secretion patterns. Methylation levels and MN/NMN patterns were compared by three genetic alteration subgroups: pseudohypoxia (PH), kinase signaling (KS), and others.

Results: A total of 178 cases were included. Methylation of PAH CpGs negatively correlated with probability for MN/NMN secretion (p < .05 for all CpGs) and positively with NMN-only secretion. NMN-only secreting tumors had significantly higher promoter methylation of PAH, DBH, and PNMT compared with MN/NMN-secreting tumors. MN/NMN-secreting PPGLs had mainly KS alterations (52.1%), whereas NMN-only PPGLs had PH alterations (41.9%). PPGLs in the PH versus KS group had gene promoter hypermethylation of PAH (p = .002), DBH (p = .02), and PNMT (p = .003).

Conclusions: Promoter methylation of genes encoding catecholamine synthesis enzymes is strongly and inversely correlated with MN/NMN patterns in PPGLs. KS and PH-related tumors have distinct methylation patterns. These results imply that methylation is a key regulatory mechanism of catecholamine synthesis in PPGLs.

Keywords: DNA methylation; catecholamines; paraganglioma; pheochromocytoma.

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References

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