Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma.

in Cancer by Anna Kaplinsky, Reut Halperin, Gadi Shlomai, Amit Tirosh

TLDR

  • The study looked at how the way a group of hormones called catecholamines are made in the body is related to how they are secreted. They found that the way these hormones are made is related to how they are secreted, and that different groups of tumors have different ways of making these hormones. This could help doctors understand more about these tumors and how to treat them.

Abstract

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. 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. 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). 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.

Overview

  • The study aims to assess the correlation between DNA methylation of catecholamine synthesis genes and MN/NMN secretion in Pheochromocytomas and paragangliomas (PPGLs).
  • The methodology used for the experiment includes extracting and calculating gene promoter methylation of catecholamine synthesis genes based on publicly available data, and performing comparisons and correlation analysis between MN ± NMN (MN/NMN), NMN only, and neither/unknown secretion patterns. The study includes a total of 178 cases.

Comparative Analysis & Findings

  • Methylation of PAH CpGs negatively correlated with probability for MN/NMN secretion 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, whereas NMN-only PPGLs had PH alterations. PPGLs in the PH versus KS group had gene promoter hypermethylation of PAH, DBH, and PNMT. 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.

Implications and Future Directions

  • The study's findings suggest that methylation is a key regulatory mechanism of catecholamine synthesis in PPGLs. The study also identifies distinct methylation patterns in KS and PH-related tumors. Future research could explore the role of methylation in the development and progression of PPGLs, and investigate the potential of targeting catecholamine synthesis enzymes for the treatment of PPGLs.
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