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Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity

Nature Reviews Cancer volume 14, pages 108–119 (2014)Cite this article

Subjects

Key Points

  • Pheochromocytomas and paragangliomas carry the highest degree of heritability (around 40%) of all human tumours and thus represent relevant models for the identification of driver mutations in cancer.

  • Genetic testing of inherited mutations allows the identification of co-occurring cancers in hereditary syndromes and screening of at-risk relatives, with an impact on health care.

  • More than 12 genes, belonging to a wide range of functional classes are mutated in the germ line or, less frequently, in somatic pheochromocytomas and paragangliomas, but many tumours remain genetically undefined.

  • Two main transcription signatures, associated with hypoxia-related signals (cluster 1) and increased kinase signalling (cluster 2), underlie the various driver mutations, revealing pathway interactions and enabling the discovery of novel predisposing genes.

  • Mutations of metabolism genes uncovered the cell growth-promoting effects of metabolism intermediates (succinate) through epigenetic (histone and DNA methylation) modulation and activation of a hypoxic response.

  • Mechanisms involved in the malignant transformation of pheochromocytomas and paragangliomas are not fully elucidated, and treatment options for these tumours are still limited.

Abstract

The neuroendocrine tumours pheochromocytomas and paragangliomas carry the highest degree of heritability in human neoplasms, enabling genetic alterations to be traced to clinical phenotypes through their transmission in families. Mutations in more than a dozen distinct susceptibility genes have implicated multiple pathways in these tumours, offering insights into kinase downstream signalling interactions and hypoxia regulation, and uncovering links between metabolism, epigenetic remodelling and cell growth. These advances extend to co-occurring tumours, including renal, thyroid and gastrointestinal malignancies. Hereditary pheochromocytomas and paragangliomas are powerful models for recognizing cancer driver events, which can be harnessed for diagnostic purposes and for guiding the future development of targeted therapies.

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Figure 1: Relative frequencies of gene mutations in germline or somatic DNA of pheochromocytomas and paragangliomas.
Figure 2: Cluster 1 mutations in paraganglial tumours.
Figure 3: Pheochromocytoma and paraganglioma susceptibility genes in cluster 2.

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Acknowledgements

The author is grateful to R. Aguiar for many suggestions and continuing support, to R. Clark for his critical reading of the manuscript, to members of the Dahia laboratory for their assistance and to the collaborators of the FP consortium for their contributions throughout the years. P.L.M.D. is supported by funds from the Cancer Prevention and Research Institute of Texas (CPRIT, RP110202), USA Department of Defense CDMRP (W81XWH-12-1-0508), Voelcker Fund and Greehey Children Cancer Research Institute (GCCRI).

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  1. Department of Medicine/Division of Hematology and Medical Oncology, Cancer Therapy and Research Center, Greehey Children Cancer Research Institute, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Lab 5053-R3, MC 7880, San Antonio, 78229–3900, TX, USA

    Patricia L. M. Dahia

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Glossary

Catecholamine

Hormone produced by the chromaffin cells of the adrenal medulla and the postganglionic fibres of the sympathetic nervous system; the main catecholamines are noradrenaline, adrenaline and dopamine.

Hypoxia

Reduced oxygen content, below physiological levels.

Pseudohypoxia

Aberrant activation of hypoxia-inducible factor and induction of its target genes, regardless of oxygen levels.

Dioxygenases

Enzymes that require oxygen and the metabolite α-ketoglutarate as co-substrates. Important members of this class are hypoxia-inducible factor prolyl hydroxylases, Jumonji histone demethylases and TET DNA hydroxylases.

Jumonji (JMJ) demethylase

Dioxygenases of the histone lysine demethylase family, which remove methyl groups of lysines in histones that control active or silent gene expression.

TET

Methyl cytosine dioxygenases that hydroxylate 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC); 5hmC produces G:C base-pair mismatches that are removed by thymine–DNA glycosylase, which results in broad DNA demethylation.

Chromaffin cells

Cells of neural crest origin thought to be the cell of origin of pheochromocytomas and sympathetic paragangliomas.

Somatostatinomas

Rare neuroendocrine tumours that produce the hormone somatostatin and arise from the pancreas, duodenum or bile ducts and can occur in isolation or associated with tumour syndromes such as neurofibromatosis type 1 or multiple endocrine neoplasia type 1.

Polycythemia

An abnormal increase in the number of circulating red cells. Occurs as a result of genetic defects (congenital) or in response to physiological or pathological conditions, including hypoxia.

Familial erythrocytosis type 4

A specific congenital form of polycythemia caused by mutations in the HIF2A gene.

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Dahia, P. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer 14, 108–119 (2014). https://doi.org/10.1038/nrc3648

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