Whether mutations in metabolic pathways contribute to the pathogenesis of cancer is controversial. 1, 2 Cancer cells have long been noted to preferentially metabolize glucose through glycolysis, a discovery that has been translated to the clinic through positron-emissiontomography imaging of 18F-deoxyglucose uptake in tumors. Moreover, recent studies have uncovered recurrent somatic mutations in four genes involved in the metabolism of mitochondrial citrate that either cause or predispose cells to become malignant.

In this issue of the Journal, Yan and colleagues3 report that 70% or more of low-grade gliomas bear mutations in one of two NADP+-dependent isocitrate dehydrogenase enzymes (IDH1 and IDH2). A similar result has been reported by Balss et al. 4 These studies follow the discoveries that mutations in succinate dehydrogenase are linked to paraganglioma and that mutations in fumarate hydratase (fumarase) lead to leiomyoma and leiomyosarcoma. 5 Recurrent mutations in the metabolic regulatory genes of these types of cancer constitute the best evidence to date that alterations in cellular metabolism contribute to the pathogenesis of human cancer.