Title: Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair.

Authors: Sulkowski, Parker L; Sundaram, Ranjini K; Oeck, Sebastian; Corso, Christopher D; Liu, Yanfeng; Noorbakhsh, Seth; Niger, Monica; Boeke, Marta; Ueno, Daiki; Kalathil, Aravind Nambiar; Bao, Xun; Li, Jing; Shuch, Brian; Bindra, Ranjit S; Glazer, Peter M

Published In Nat Genet, (2018 Aug)

Abstract: The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively1-3. Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors. These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic.

PubMed ID: 30013182

MeSH Terms: No MeSH terms associated with this publication