Fumarate hydratase and other genetic insights into tumour metabolism


Year:

Session type:

Ian Tomlinson

University of Oxford, UK

Abstract

Although the use of anaerobic metabolism by normoxic tumour cells has been established for many years, recent insights have been provided by the finding that mutations in three components of the Krebs cycle succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase cause the growth of specific benign and malignant tumours.

This presentation focuses on the role played by germline fumarate hydratase mutations in the development of papillary renal cell cancers and leiomyomas. It seems likely that one consequence of these mutations is accumulation of succinate and fumarate, leading to inhibition of alpha-ketoglutarate-dependent enzymes. Specifically, the HIF prolyl hydroylases appear to be inhibited in this way, leading to activation of the hypoxia pathway in fumarate hydratase-mutant tumours. Recent data from animal models suggest, however, that additional effects of fumarate hydratase mutations are required for tumours to grow.