Abstract
Simple SummaryPheochromocytomas and paragangliomas are rare neuroendocrine tumors that are often hereditary. Although research has advanced considerably, significant gaps still persist in understanding risk factors, predicting metastatic potential and treating aggressive tumors. The study of rare mutations can provide new insights into how pheochromocytomas and paragangliomas develop. In this review, we provide examples of such rare events and how they can inform our understanding of the spectrum of mutations that can lead to these tumors and improve our ability to provide a genetic diagnosis.Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in cancer. In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior.
Highlights
Pheochromocytomas and paragangliomas (PPGLs) are predominantly benign, and malignancy is only established by the detection of metastasis, which occurs in approximately 30% of paragangliomas and 10–15% of pheochromocytomas
Cluster 1 consists of the pseudohypoxia pathway and includes tumors with either germline or somatic mutations in VHL, SDHA/B/C/D/AF2, EPAS1, EGLN1, EGLN2, FH, SLC25A11, and MDH2 (Figure 1B)
In a study of six tumor samples from five cyanotic congenital heart disease (CCHD) patients, including five sympathetic PPGLs and one carotid body paraganglioma (CB-PGL), we found that four out of five sympathetic PPGLs displayed a somatic EPAS1 mutation affecting either alanine or proline [75]
Summary
Patients with PPGLs should be engaged in genetic testing [1,35]. The relevance of genetic diagnosis is demonstrated by its positive impact on patient outcomes [46]. Variant classification requires careful interpretation of a combination of information including (a) the type of variant, (b) the frequency of the variant, (c) the occurrence of the variant in clinically-related databases, (d) literature citations of the variant, (e) functional evaluation of the variant, (f) in silico predictions of variant effect, (g) analysis of co-segregation of disease in the family, (h) concordance with phenotype, and (i) co-occurrence of pathogenic variants [47] The latter is an increasingly likely scenario observed in NGS-based studies, which adds to the complexity of interpreting variant relevance [49]; this subject will not be discussed in this brief review. Functional studies are recommended to assess the pathogenicity of variants, which may be resource-intensive [18,22,47]
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