Comprehensive molecular characterization and response to therapy in fumarate hydratase–deficient renal cell carcinoma

Jack P. Gleeson, Ines Nikolovski, Renzo Dinatale, Mark Zucker, Andrea Knezevic, Sujata Patil, Yasser Ged, Ritesh R. Kotecha, Natalie Shapnik, Samuel Murray, Paul Russo, Jonathan Coleman, Chung Han Lee, Zsofia K. Stadler, A. Ari Hakimi, Darren R. Feldman, Robert J. Motzer, Ed Reznik, Martin H. Voss, Ying Bei ChenMaria I. Carlo

Research output: Contribution to journalArticlepeer-review


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 ¼ 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 ¼ 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n ¼ 18, ORR 44%), VEGF monotherapy (n ¼ 15, ORR 20%), checkpoint inhibitor therapy (n ¼ 8, ORR 0%), and mTOR monotherapy (n ¼ 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.

Original languageEnglish (US)
Pages (from-to)2910-2919
Number of pages10
JournalClinical Cancer Research
Issue number10
StatePublished - May 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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