Rethinking pheochromocytomas and paragangliomas from a genomic perspective

Abstract

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors of neural crest origin. These tumors are caused by germline or somatic mutations in known susceptibility genes in up to 70% of cases. Over the past few years, the emergence of high-throughput technologies has enabled the unprecedented characterization of genomic alterations in PCC/PGL, and has improved our understanding of the molecular mechanisms that distinguish the different tumor subtypes. Integrated genomic analyses have shown that the mutation status of PCC/PGL susceptibility genes strongly correlates with multi-omics data. These observations not only emphasize the role of the long-standing susceptibility genes as the main drivers of PCC/PGL tumorigenesis, but also illustrate the functional interdependence between genomic and epigenomic alterations. In this review, we discuss the genomic landscape underlying PCC/PGL, its functional consequences for tumorigenesis and tumor progression, and the potential clinical relevance of this knowledge for the application of precision medicine for patients with PCC/PGL.

Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma

“…Multiple endocrine neoplasia type 2 (MEN2)-associated PCC is usually present in late teenage or young adulthood, whereas those in NF1 present usually in mid-to late adulthood. 5,9 However, in both syndromes, PPGL can present during childhood. SDHC-, SDHAF2-, MAX-, and TMEM127-associated PPGLs may rarely present during childhood.…”

“…The PPGLs in SDHB mutation carriers are usually extra-adrenal TAPGL followed by adrenal PCC and head-and-neck PGL (HNPGL). 5,12 In SDHD, tumors are mostly HNPGL, and less common are adrenal PCC and extra-adrenal TAPGL. 5,12 In SDHC and SDHAF2, tumors are predominantly HNPGL, though they are often thoracic PGL (SDHC).…”

“…5 In patients who present during the first decade of life, VHL mutations account for the most PPGLs, even among apparently sporadic tumors. Multiple endocrine neoplasia type 2 (MEN2)-associated PCC is usually present in late teenage or young adulthood, whereas those in NF1 present usually in mid-to late adulthood.…”

“…Cluster 1 is enriched with genes that are associated with the hypoxic response, and cluster 2 contains tumors that activate kinase signaling and protein translation. 5 Cluster 1 genes include VHL, components of the SDH complex (SDHA, SDHB, SDHC, and SDHD, as well as SDHAF2), FH, PHD1, PHD2, HIF2A, and MHD2. 5 Cluster 2, a more heterogeneous group, encompasses PPGLs with RET, NF1, TMEM127, and MAX mutations.…”

“…5 Cluster 1 genes include VHL, components of the SDH complex (SDHA, SDHB, SDHC, and SDHD, as well as SDHAF2), FH, PHD1, PHD2, HIF2A, and MHD2. 5 Cluster 2, a more heterogeneous group, encompasses PPGLs with RET, NF1, TMEM127, and MAX mutations.…”