Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity

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.

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…47,65,78,79 Although familial PCC/PGL syndromes were thought to predispose only to PCCs and PGLs, different tumors such as GISTs, RCCs, and PAs have expanded the tumor spectrum associated with SDH mutations. 77 No patient has developed all tumor types, indicating an incomplete penetrance of the syndrome similar to that seen in the Carney triad. 64 To explain the issue of cell specificity, Hoekstra and Bayley 69 pointed toward differences of cell types either in their requirements for adenosine triphosphate, redox agents, and TCA cycle-generated metabolic intermediates during development and/or throughout life or in their response to cancerous transformation.…”

“…73,74 In addition, some research suggests that germ-line and somatic interactions could account for the clinical variability observed among carriers of an identical SDH germ-line mutation, including those within the same family. 46,[75][76][77] In this context, the occurrence of SDH-related tumors is extremely rare in the absence of a germ-line mutation. Indeed, only a few cases have been reported: one extra-adrenal PGL harboring a somatic SDHB mutation (c.299C>T, p.Ser100Phe) and a somatic SDHD mutation in a PCC (c.242C>T, p.Pro81Leu), both displaying LOH; one PA harboring two somatic SDHA mutations (c.725_736del; c.989_990insTA); and tumors from four patients with the Carney triad showing a DNA hypermethylation of SDHC.…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…Some of these driver genes are only mutated at the germ line level, while others can be mutated either at the germ line or somatic level. A third group of driver genes are only mutated somatically 1,2,48 . The relative frequency of overall mutations and specific germ line and/ or somatic events for each of these genes varies (TABLE 1).…”

Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations

“…Hereditary PGL syndrome is caused most frequently by genes encoding succinate dehydrogenase (SDH) subunits or co‐factors ( SDHA/B/C/D/AF2 genes). Other associated genes are RET , NF1 , VHL , HIF2A , FH , TMEM127 and MAX 6 7. In the Netherlands, mutations in SDHD, SDHB and SDHAF2 are responsible for most hereditary cases.…”

“…In contrast, SDHB mutation carriers are reported to develop single PGLs and metastatic PGLs more frequently8, 9, 10, 11, 12. Recently it has become clear that the SDHB ‐linked tumour syndrome not only comprises PGLs and phaeochromocytomas, but also non‐paraganglionic tumours such as renal clear cell carcinoma, gastrointestinal stromal tumours (GISTs) and pituitary tumours6, 7, 8, 9, 10, 11, 12.…”