Integrated Molecular Characterization of Fumarate Hydratase-deficient Renal Cell Carcinoma

Clin Cancer Res. 2021 Mar 15;27(6):1734-1743. doi: 10.1158/1078-0432.CCR-20-3788. Epub 2021 Jan 7.


Purpose: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC.

Experimental design: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded.

Results: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade-based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03).

Conclusions: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology*
  • DNA Methylation
  • Epigenesis, Genetic*
  • Female
  • Follow-Up Studies
  • Fumarate Hydratase / deficiency*
  • Fumarate Hydratase / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Metastasis
  • Prognosis
  • Retrospective Studies
  • Survival Rate
  • Young Adult


  • Biomarkers, Tumor
  • Immune Checkpoint Inhibitors
  • Fumarate Hydratase