Krebs Cycle-Deficient Hereditary Cancer Syndromes are Defined by Homologous Recombination DNA Repair Defects

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 the fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes encoding Krebs cycle enzymes, leading to elevated levels of fumarate and succinate, respectively(1–3). 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, 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 pointing to a new therapeutic approach for advanced HLRCC and SDH PGL/PCC, both incurable when metastatic.