Patrick J Pollard
Posters-Accepted Abstracts: Metabolomics
Cancer associated mutations have been identified in the metabolic genes Succinate dehydrogenase (SDH), Fumarate hydratase (FH) and Isocitrate dehydrogenase (IDH), advancing and challenging our understanding of cellular function and disease mechanisms and providing direct links between dysregulated metabolism and cancer. Some striking parallels exist in the cellular consequences of the genetic mutations within this triad of cancer syndromes, including accumulation of oncometabolites and competitive inhibition of 2-oxoglutarate-(2OG)-dependent dioxygenases, particularly hypoxia-inducible factor prolyl hydroxylases (HIF-PHDs), JmjC domain-containing histone demethylases (part of the JMJD family) and the TET (ten-eleven translocation) family of 5methyl Cytosine (5mC) DNA hydroxylases. These lead to activation of HIF-dependent oncogenic pathways, inhibition of histone and DNA demethylation and hydroxylation of 5 mC. Mutations in FH, resulting in loss of enzyme activity, predispose affected individuals to a rare cancer, hereditary leiomyomatosis and renal cell cancer (HLRCC), characterized by benign smooth muscle cutaneous and uterine tumors (leiomyomata) and an aggressive form of collecting duct and Type 2 papillary renal cancer. Interestingly, loss of FH activity results in the accumulation of high levels of fumarate that can lead to the non-enzymatic modification of cysteine residues in multiple proteins (succination) and in some cases to their disrupted function; an example being succination of KEAP1 resulting in constitutive NRF2 expression. Here we consider that the study of rare diseases such as HLRCC, combining analyses of human tumours and cell lines with in vitro and in vivo murine models has provided novel insights into cancer biology, links associated with dysregulated metabolism, obesity and diabetes and represents a useful paradigm for cancer research.