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Paraganglioma and phaeochromocytoma: from genetics to personalized medicine

Nature Reviews Endocrinology volume 11, pages 101–111 (2015)Cite this article

Subjects

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

Abstract

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.

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Figure 1: Timescale of the discovery of PPGL susceptibility genes.
Figure 2: Algorithms for PPGL genetic testing by Sanger or by next-generation sequencing.
Figure 3: From integrative genomics studies to molecular targeted therapies.

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Acknowledgements

The authors thank Mrs Julie Sappa for English-language assistance (service provided by Alex Edelman & Associates). The research led by A.-P.G.-R. and J.F. is supported by the Programme Hospitalier de Recherche Clinique grant COMETE 3 (AOM 06 179), by grants from the Agence Nationale de la Recherche (ANR 08 GENOPATH 029 MitOxy & ANR 2011-JCJC-00701 MODEOMAPP) and from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259735.

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Authors and Affiliations

  1. INSERM, UMR 970, Paris Cardiovascular Research Centre, Paris, F-75015, France

    Judith Favier

  2. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité d'Hypertension Artérielle, Paris, F-75015, France

    Laurence Amar

  3. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, F-75006, France

    Anne-Paule Gimenez-Roqueplo

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J.F. researched data for the article, contributed to discussion of the content, and reviewed and edited the manuscript before submission. L.A. researched data for the article and contributed to discussion of the content. A.-P.G.-R. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and edited the article before submission.

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Correspondence to Anne-Paule Gimenez-Roqueplo.

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Favier, J., Amar, L. & Gimenez-Roqueplo, AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol 11, 101–111 (2015). https://doi.org/10.1038/nrendo.2014.188

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