Evaluating a possible association between promoter methylation level of genes encoding catecholamine metabolizing enzymes and metanephrine secretion in pheochromocytoma and paraganglioma (A10)

Introduction: Paragangliomas (PPGLs) are rare neuroendocrine tumors that may secrete
catecholamines and their metabolites (metanephrines [MN], normetanephrine [NMN]). Secretion
patterns differ by adrenal/extra-adrenal origin and genetic alteration. Catecholamines synthesis is
carried by phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), aromaticL-aminoacid
decarboxylase (AADC), dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase
(PNMT). However, their regulation in PPGL is not entirely understood.

Aim(s): Assess whether epigenetic gene regulation of catecholamine synthesis leads to distinct MN and NMN secretion patterns in PPGLs.

Materials and methods: PPGL methylation data from 178 samples were collected from a
public database. We analysed CpGs methylation of PAH, TH, AADC, DBH, and PNMT and compared MN and NMN secretion and genetic alteration subgroups (pseudohypoxia [PH], kinase signaling [KS]) by methylation levels.

Results: PAH and DBH CpGs methylation negatively correlated with probability for
MN/NMN secretion but positively correlated with NMN-only secretion, with similar trends for TH, PNMT, and DDC. NMN-only secreting tumors had significantly higher promoter methylation of PAH, DBH, and PNMT, compared with MN/NMN secreting tumors. Comparison by genetic alteration demonstrated that tumors with PH alterations had relative hypermethylation of the gene promoters of PAH (p=0.002), DBH (p=0.02), and PNMT (p=0.003) compared with KS.

Conclusion: Promoter methylation of genes encoding for catecholamine synthesis enzymes is strongly and inversely associated with MN/NMN secretion patterns in PPGLs. KS and PH-related tumors are associated with distinct methylation patterns. This implies that methylation is a key regulatory mechanism of PPGL catecholamine secretion.

Keywords: ppgl, methylation, catecholamine, pseudohypokia, metanephrine, kinase signaling,
pheochromocytoma, paraganglioima