Endocrine Abstracts (2017) 50 S5.1 | DOI: 10.1530/endoabs.50.S5.1

SDH mutations in tumourigenesis

Eamonn Maher


University of Cambridge, Cambridge, UK.


Seventeen years ago, germline mutations in the SDHD gene were reported to be associated with familial head and neck paraganglioma (HNPGL) and, subsequently, sporadic and familial phaeochromocytoma and paraganglipoma (PPGL). Thereafter germline mutations in other succinate dehydrogenase subunit genes (SDHB, SDHC, SDHA) were also found to predispose to HNPGL and PPGL. Succinate dehydrogenase has critical roles in the Krebs cycle and respiratory chain electron-transport (as part of mitochondrial complex II) and disease associated germline SDH subunit (SDHx) mutations are loss of function mutations with SDH-associated tumours demonstrating biallelic inactivation of the relevant SDHx subunit. SDH-mutated tumours show increased expression of hypoxia-inducible genes, and genomic and histone hypermethylation and these effects appear to result, in part, through succinate-mediated inhibition of α-ketoglutarate-dependent dioxygenases. Though the range of tumours associated with SDHx has expanded beyond HNPGL/PPGL to include renal cell carcinoma, gastrointestinal stromal tumours (GIST) and pituitary adenomas-associated tumours, the lifetime tumour risks in individuals who carry a germline SDHx mutation are significantly lower than originally described raising questions about the optimum screening protocol for asymptomatic mutation carriers. Characterisation of germline SDHx mutations clarifies inheritance patterns (all are inherited in an autosmal dominant trait but SDHD mutations generally only cause disease when paternally inherited), malignancy risk (high with SDHB mutations) and risk for specific tumour types (this varies according to the SDHx subunit involved and may vary with specific SDHD/SDHB mutations). Though further progress is required in our knowledge SDH-related tumourigenesis and for personalised tumour risk prediction and management, SDHx mutation analysis is now routine in patients with PPGL, HNPGL and wild-type GIST and SDH-associated neoplasia provides a paradigm for investigating the role of disordered cellular metabolism in tumourigenesis.

Review: Baysal B E, Maher E R. Endocr Relat Cancer. 2015;22:T71-82

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