Mutations in FH or SDH drive tumorigenesis in the hereditary cancer syndromes HLRCC and SDH PGL/PCC.

  • Major finding: Mutations in FH or SDH drive tumorigenesis in the hereditary cancer syndromes HLRCC and SDH PGL/PCC.

  • Mechanism: FH and SDH mutations lead to accumulation of fumarate or succinate that inhibit KDM4A/B to suppress HR.

  • Impact: Impaired homologous recombination may render HLRCC or SDH PGL/PCC tumors sensitive to PARP inhibitors.

The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase–related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are caused by loss-of-function mutations in the Krebs cycle enzymes FH (encoding fumarate hydratase; in HLRCC) or SDHA, SDHAF1, SDHB, SDHC, or SDHD (which encode succinate dehydrogenases; in SDH PGL/PCC). When the second functional allele is lost, the excess accumulation of fumarate or succinate results in inhibition of α-ketoglutarate (αKG)-dependent dioxygenases to drive the cancer syndrome. In glioma, IDH1/2 mutations lead to inhibition of αKG-dependent enzymes, which results in defects in homologous recombination (HR). This led Sulkowski and colleagues to hypothesize that fumarate- or succinate-mediated inhibition of αKG-dependent enzymes might also suppress HR in HLRCC and SDH PGL/PCC. Consistent with this hypothesis, high levels of fumarate or succinate were associated with elevated DNA double-strand breaks (DSB) in tumors from patients with HLRCC and SDH PBL/PCC compared with corresponding normal tissue. Deficiencies in fumarate hydratase or succinate dehydrogenase led to reduced DNA repair by HR, resulting in increased DNA DSBs and DNA-damage response foci. Mechanistically, fumarate and succinate competitively inhibited the lysine demethylases KDM4A and KDM4B, both of which are αKG-dependent dioxygenases involved in regulating DNA repair, resulting in suppression of HR. Impaired HR rendered FH- or SDH-deficient cells sensitive to PARP inhibitor treatment in vitro and in vivo. Taken together, these findings elucidate a mechanism by which deficiencies in FH or SDH promote HLRCC and SDH PGL/PCC and suggest the potential for PARP inhibitor therapies in patients with these hereditary cancer syndromes.

Sulkowski PL, Sundaram RK, Oeck S, Corso CD, Liu Y, Noorbakhsh S. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet 2018 Jul 16 [Epub ahead of print].

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©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.