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

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.

• Authors: Parker L Sulkowski, Ranjini K Sundaram, Sebastian Oeck, Christopher D Corso, Yanfeng Liu, Seth Noorbakhsh, Monica Niger, Marta Boeke, Daiki Ueno, Aravind Nambiar Kalathil, Xun Bao, Jing Li, Brian Shuch, Ranjit S Bindra, Peter M Glazer
• Journal: Nature genetics (Nat Genet) Vol. 50 Issue 8 Pg. 1086-1092 (08 2018) ISSN: 1546-1718 [Electronic] United States
• PMID: 30013182 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fumarates
• Succinic Acid

Topics

• Adrenal Gland Neoplasms (genetics)
• Cell Line
• Cell Line, Tumor
• Citric Acid Cycle (drug effects, genetics)
• DNA Breaks, Double-Stranded
• Fumarates (pharmacology)
• Germ-Line Mutation
• HEK293 Cells
• Humans
• Leiomyomatosis (genetics)
• Neoplastic Syndromes, Hereditary (genetics)
• Pheochromocytoma (genetics)
• Recombinational DNA Repair
• Skin Neoplasms (genetics)
• Succinic Acid (pharmacology)
• Uterine Neoplasms (genetics)