15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations

Abstract

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of a-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs.

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

“…An increasing number of genes can be responsible for development of both tumour types individually or in association, which suggests a closer connection than previously appreciated [86][87][88][89] . In addition to VHL, SDH 90,91 , FH 92 and TMEM127 (REFS 93,94), genes can also be mutated in renal carcinomas either with or without co-occurrence of PPGL.…”

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas

“…Familial susceptibility to PGLs caused by these genes can be passed on by either parent, but the tumors will only develop if the mutation is inherited from the father. The mechanism is not fully understood but apparently differs from maternal imprinting of other genes [14]. This phenomenon poses challenges in identifying germline patients through family history alone as generations may be skipped when transmission is maternal.…”

Nasal Cavity Paraganglioma: Literature Review and Discussion of a Rare Case

“…Genetic analyses disclosed the role of mutations in the succinate dehydrogenase (SDH) genes in familial and nonfamilial paragangliomas [19]. Succinate dehydrogenase enzymatic activity is lost partially or completely in the tumor, despite the typo of gene mutation 8.…”

“…Pediatric paragangliomas insinuate genetic predisposition [4] and screening for multiple germline mutations can be performed, such as SDHB and SDHD, which are the most important for predicting a malignant nature [14,19]. …”