Journal Article

Paraganglioma and phaeochromocytoma: from genetics to personalized medicine

Favier, Judith, Gimenez-Roqueplo, Anne-Paule, Amar, Laurence

2015

Overview

Key Points Over half of all phaeochromocytoma and/or paraganglioma (PPGL) can be attributed to genetic alterations 80% of inherited PPGLs are caused by a germline mutation in VHL or the SDHx group of genes Genetic testing is indicated for all patients with PPGLs, as identification of the underlying mutation guides patient management and genetic counselling Gene expression profiling can be used to classify PPGLs, assigning them to either an angiogenic cluster or a kinase signalling cluster, each of which has specific treatment targets DNA methylation profiling has revealed a hypermethylated cluster that is specific to tumours related to the SDHx genes and FH that accounts for the malignant and noradrenergic phenotype of tumours related to mutations in these genes Genomic studies of PPGLs are generating important findings that should pave the way for personalized medicine for affected patients During the past 15 years, our understanding of phaeochromocytoma and/or paraganglioma and the management of affected patients and their relatives have been revolutionized. Particular progress has been made in our understanding of the genetic changes underlying these tumours. This Review discusses the key advances that have occurred over this period. Paragangliomas and phaeochromocytomas are neuroendocrine tumours whose pathogenesis and progression are very strongly influenced by genetics. A germline mutation in one of the susceptibility genes identified so far explains ∼40% of all cases; the remaining 60% are thought to be sporadic cases. At least one-third of these sporadic tumours contain a somatic mutation in a predisposing gene. Genetic testing, which is indicated in every patient, is guided by the clinical presentation as well as by the secretory phenotype and the immunohistochemical characterization of the tumours. The diagnosis of an inherited form drives clinical management and tumour surveillance. Different 'omics' profiling methods have provided a neat classification of these tumours in accordance with their genetic background. Transcriptomic studies have identified two main molecular pathways that underlie development of these tumours, one in which the hypoxic pathway is activated (cluster 1) and another in which the MAPK and mTOR (mammalian target of rapamycin) signalling pathways are activated (cluster 2). DNA methylation profiling has uncovered a hypermethylator phenotype in tumours related to SDHx genes (a group of genes comprising SDHA , SDHB , SDHC , SDHD and SDHAF2 ) and revealed that succinate acts as an oncometabolite, inhibiting 2-oxoglutarate-dependent dioxygenases, such as hypoxia-inducible factor prolyl-hydroxylases and histone and DNA demethylases. 'Omics' data have suggested new therapeutic targets for patients with a malignant tumour. In the near future, new 'omics'-based tests are likely to be transferred into clinical practice with the goal of establishing personalized medical management for affected patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/420/2489/144 / 692/699/2743/1459/1963 / 692/700/139/1512 / 692/700/565 / Adrenal Gland Neoplasms - genetics / Adrenal Gland Neoplasms - pathology / Cancer / DNA methylation / Endocrinology / Genetic testing / Humans / Medicine & Public Health / Mutation / Neuroendocrine tumors / Neuroendocrine Tumors - genetics / Neuroendocrine Tumors - pathology / Oncology, Experimental / Paraganglioma - genetics / Paraganglioma - pathology / Pheochromocytoma - genetics / Pheochromocytoma - pathology / Precision medicine / Precision Medicine - methods / review-article