Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma

Clin Cancer Res. 2021 May 15;27(10):2910-2919. doi: 10.1158/1078-0432.CCR-20-4367. Epub 2021 Mar 3.


Purpose: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking.

Experimental design: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included.

Results: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively.

Conclusions: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Antineoplastic Combined Chemotherapy Protocols
  • Biomarkers, Tumor*
  • Carcinoma, Renal Cell / diagnosis
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / mortality
  • Computational Biology
  • DNA Copy Number Variations
  • Female
  • Fumarate Hydratase / deficiency*
  • Germ-Line Mutation
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Retrospective Studies
  • Treatment Outcome
  • Young Adult


  • Biomarkers, Tumor
  • Fumarate Hydratase