Format

Send to

Choose Destination
Nat Genet. 2018 Aug;50(8):1086-1092. doi: 10.1038/s41588-018-0170-4. Epub 2018 Jul 16.

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

Author information

1
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
3
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany.
4
Southeast Radiation Oncology and Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.
5
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
6
Department of Urology, Yale University School of Medicine, New Haven, CT, USA.
7
Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
8
Department of Urology, Yale University School of Medicine, New Haven, CT, USA. brian.shuch@yale.edu.
9
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA. ranjit.bindra@yale.edu.
10
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. ranjit.bindra@yale.edu.
11
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA. peter.glazer@yale.edu.
12
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. peter.glazer@yale.edu.

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.

PMID:
30013182
PMCID:
PMC6072579
DOI:
10.1038/s41588-018-0170-4
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center