PRECISION MEDICINE: AN UPDATE ON GENOTYPE/BIOCHEMICAL PHENOTYPE RELATIONSHIPS IN PHEOCHROMOCYTOMA/PARAGANGLIOMA PATIENTS

Abstract

Objective: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors known to produce and secrete high levels of circulating catecholamines and their metabolites. The biochemical characteristics of these tumors can be used to divide them into three major phenotypes. The adrenergic, noradrenergic and dopaminergic phenotypes are defined by predominant elevations in epinephrine and metanephrine, norepinephrine and normetanephrine, and dopamine and 3-methoxytyramine, respectively. There are over 15 well-identified tumor-susceptibility genes responsible for approximately 40% of the cases. The objective of this review article is to outline specific genotype/biochemical phenotype relationships.

Methods: Literature review.

Results: None.

Conclusion: Biochemical phenotype of PPGL is determined by the underlying genetic mutation and the associated molecular pathway. Identification of genotype/biochemical relationships is valuable in prioritizing testing for specific genes, making treatment decisions and monitoring disease progression.

Abbreviations: 3-MT = 3-methoxytyramine; EPAS1 = endothelial pas domain protein 1; FH = fumarate hydratase; HIF2A = hypoxia inducible factor type 2A; MEN2 = multiple endocrine neoplasia type 2; NF1 = neurofibromatosis type 1; PNMT = phenylethanolamine N-methyltransferase; PPGL = pheochromocytoma and paraganglioma; RET = rearranged during transfection; SDH = succinate dehydrogenase; SDHAF2 = succinate dehydrogenase complex assembly factor 2; TCA = tricarboxylic acid; TH = tyrosine hydroxylase; TMEM127 = transmembrane protein 127; VHL = von Hippel-Lindau.

Fig. 1.

(A) Biosynthetic pathway of catecholamines. Norepinephrine vesicular storage granules are found in noradrenergic neurons and chromaffin cells of the adrenal medulla. Norepinephrine from these granules can passively leak back into the cytoplasm and be converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT). (B) Main pathways of catecholamine metabolism. Most of the norepinephrine (NE) released into the synaptic cleft translocates back into the neurons to either be sequestered in vesicles or metabolized. The remaining circulating NE is acted upon by the enzyme catechol-O-methyltransferase (COMT), restricted to extraneuronal tissues. Epinephrine (EPI) is mainly metabolized by COMT in the chromaffin cells of the adrenal medulla. All catecholamine metabolites, apart from vanillylmandelic acid (VMA) and homovanillic acid (HVA), are sulfate-conjugated by sulfotransferase type 1A3 (SULT1A3) in the gastrointestinal tract wall (GIT) prior to excretion. *Key metabolites that serve as disease markers. ADH = alcohol dehydrogenase; DA = dopamine; DBH = dopamine β-hydroxylase; DHPG = 3,4-dihydroxyphenylglycol; DOPAC = 3,4-dihydroxyphenylacetic acid; L-AADC = L-amino acid decarboxylase; MAO = monoamine oxidase; MHPG = 3-methoxy-4-hydroxyphenylglycol; MHPG-SO₄ = 3-methoxy-4-hydroxyphenylglycol sulfate; MN = metanephrine; MN-SO₄ = metanephrine sulfate; 3-MT = 3-methoxytyramine; NMN = normetanephrine; NMN-SO₄ = normetanephrine sulfate; PNMT = phenylethanolamine N-methyltransferase; TH = tyrosine hydroxylase; VMAT = vesicular monoamine transporter.

Fig. 2.

Illustration of how a genetic mutation influences the biochemical phenotype of a tumor.

Fig. 3.

Involvement of the hypoxia-inducible factor (HIF) signaling pathway and tricarboxylic acid (TCA) cycle substrates in determining the noradrenergic phenotype of the tumor. Mutations in genes encoding HIF-α, tumor suppressor von Hippel-Lindau (pVHL), succinate dehydrogenase (SDH), fumarate hydratase (FH), and malate dehydrogenase (MDH)2 lead to stabilization of HIF-α. TCA cycle substrate accumulation hypermethylates the promoter region of phenylethanolamine N-methyltransferase (PNMT) and decreases its expression. *Genes encoding these proteins are implicated in pheochromocytoma and paraganglioma pathogenesis. ACO = aconitase; CS = citrate synthase; IDH = isocitrate dehydrogenase; KGDH = ketoglutarate dehydrogenase; succinyl-CoA = succinyl coenzyme A; SUCLG = succinyl-CoA synthetase.

Fig. 4.

Genotype-biochemical phenotype/location associations. Note: this chart may be used as a guide for time-sensitive genotype-dependent treatment options and targeted genetic screening when next-generation sequencing is not available. HNPGL = head and neck paraganglioma; TAPPGL = thoracic abdominal and pelvic paraganglioma.