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

• Published in: Nature genetics Vol. 50; no. 8; pp. 1086 - 1092
• Main 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2018; Nature Publishing Group
• Subjects: 13; 13/106; 13/44; 13/89; 14; 14/1; 14/63; 631/208; 631/67; 631/67/589; 64/60; 82/29; Adenosine diphosphate; Adrenal Gland Neoplasms - genetics; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer; Cancer cells; Cancer genetics; Cancer metastasis; Cancer Research; Cell Line; Cell Line, Tumor; Citric Acid Cycle - drug effects; Citric Acid Cycle - genetics; Dehydrogenases; Deoxyribonucleic acid; Disorders; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA repair; Enzymes; Epigenetics; Fibroids; Fumarase; Fumarates - pharmacology; Gene Function; Genes; Germ-Line Mutation; HEK293 Cells; Homologous recombination; Homology; Human Genetics; Humans; Ionizing radiation; Kidney cancer; Krebs cycle; Leiomyomatosis - genetics; Letter; Medical schools; Metabolites; Metastases; Monosaccharides; Mutation; Neoplastic Syndromes, Hereditary - genetics; Paraganglioma; Pheochromocytoma; Pheochromocytoma - genetics; Poly(ADP-ribose) polymerase; Recombinational DNA Repair; Renal cell carcinoma; Repair; Ribose; Skin Neoplasms - genetics; Succinate dehydrogenase; Succinic Acid - pharmacology; Tricarboxylic acid cycle; Tumor cells; Tumors; Uterine Neoplasms - genetics
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-018-0170-4

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, 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, 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. High levels of fumarate or succinate suppress the homologous-recombination DNA-repair pathway in cancer cells that are deficient for FH or SDH, respectively. These tumor cells are vulnerable to PARP inhibitors.