Precision medicine in pheochromocytoma and paraganglioma: current and future concepts

Abstract

Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome-related tumours. Genotype-tailored treatment options, follow-up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large-scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.

Keywords: cancer metabolism; neuroendocrine tumours; paraganglioma; personalized medicine; pheochromocytoma; precision medicine.

Fig. 1

Description of genes involved in pheochromocytoma and paraganglioma tumourigenesis grouped in molecular clusters, and the estimated overall frequency of pathogenic mutations in these diseases.

Fig. 2

Summary of the genetic and molecular characteristics of pheochromocytoma and paraganglioma in the three different clusters.

Fig. 3

(a–c) Current and future perspectives of precision medicine in pheochromocytoma and paraganglioma stratified by molecular subgroup.

Fig. 4

Proposed evolution of pheochromocytoma and paraganglioma from tumour initiation to metastatic seed. Genetic heterogeneity may occur within tumours as well as between different tumour lesions. SNA, somatic copy number alterations.