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Role of epigenetic regulation on catecholamine synthesis in pheochromocytoma and paraganglioma.
- Source :
-
Cancer (0008543X) . Oct2024, Vol. 130 Issue 19, p3289-3296. 8p. - Publication Year :
- 2024
-
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. This study aimed to assess a possible association between the genetic background of pheochromocytoma/paraganglioma (PPGL) and gene regulation of catecholamine synthesis enzymes. We found that kinase signaling‐related and pseudohypoxia‐related alterations have distinct methylation patterns, implying methylation as a key regulatory mechanism of catecholamine synthesis in PPGLs. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0008543X
- Volume :
- 130
- Issue :
- 19
- Database :
- Academic Search Index
- Journal :
- Cancer (0008543X)
- Publication Type :
- Academic Journal
- Accession number :
- 179411603
- Full Text :
- https://doi.org/10.1002/cncr.35426