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Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity
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Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity
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Journal Article
Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity
2014
Overview
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.
Patricia L. M. Dahia gives an overview of insights learned from the study of pheochromocytomas and paragangliomas, which carry the highest degree of heritability of all human tumours.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
