Advances in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) research

Semin Cancer Biol. 2020 Apr:61:158-166. doi: 10.1016/j.semcancer.2019.10.016. Epub 2019 Nov 2.


Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. It is caused by a germline amorphic allele of the FH gene, which encodes the TCA cycle enzyme, fumarate hydratase (FH). HLRCC patients are genetically predisposed to develop skin leiomyomas, uterine fibroids, and the aggressive kidney cancer of type 2 papillary morphology. Loss-of-heterozygocity at the FH locus that cause a complete loss of FH enzymatic function is always detected in these tumor tissues. Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH-/- tumor cells. These treatment strategies include ferroptosis induction, oxidative stress promotion, and metabolic alteration. As the fundamental biology of HLRCC continues to be uncovered, these treatment strategies continue to be refined and may one day lead to a strategy to prevent disease onset among HLRCC patients. With a more complete picture of HLRCC biology, the safe translation of experimental treatment strategies into clinical practice is achievable in the foreseeable future.

Keywords: FH; Ferroptosis; Fumarate; HLRCC; Hereditary cancer syndrome; Hypoxia inducible factor; Iron homeostasis; KEAP1; Kidney cancer; NRF2; Papillary renal cell carcinoma; RCC; Succination.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Biomarkers, Tumor
  • Disease Management
  • Disease Susceptibility
  • Fumarate Hydratase / genetics
  • Genes, Tumor Suppressor
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genomics / methods
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Leiomyomatosis / diagnosis
  • Leiomyomatosis / etiology*
  • Leiomyomatosis / metabolism
  • Leiomyomatosis / therapy
  • Mutation
  • Neoplastic Syndromes, Hereditary / diagnosis
  • Neoplastic Syndromes, Hereditary / etiology*
  • Neoplastic Syndromes, Hereditary / metabolism
  • Neoplastic Syndromes, Hereditary / therapy
  • Proteome
  • Signal Transduction
  • Skin Neoplasms / diagnosis
  • Skin Neoplasms / etiology*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / therapy
  • Translational Research, Biomedical
  • Uterine Neoplasms / diagnosis
  • Uterine Neoplasms / etiology*
  • Uterine Neoplasms / metabolism
  • Uterine Neoplasms / therapy


  • Biomarkers, Tumor
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proteome
  • Fumarate Hydratase

Supplementary concepts

  • Hereditary leiomyomatosis and renal cell cancer