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Published on: January 22, 2013
Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma
Jack P Gleeson1, Ines Nikolovski2, Renzo Dinatale3
1Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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.
Insights
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is aggressive, often linked to hereditary syndromes. Combination mTOR/VEGF therapy shows promise, while immunotherapy alone yielded no response in this rare cancer.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive subtype of renal cell carcinoma.
- It is strongly associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.
- Limited evidence exists regarding the efficacy of systemic therapies for FH-RCC.
Purpose of the Study:
- To investigate the clinical and genomic characteristics of FH-RCC.
- To evaluate the response rates of systemic therapies in patients with metastatic FH-RCC.
- To identify co-occurring mutations and genomic alterations in FH-RCC.
Main Methods:
- Retrospective analysis of patients with metastatic FH-RCC.
- Inclusion criteria: pathogenic germline or somatic FH mutation with immunohistochemical evidence of FH loss.
- Next-generation sequencing (NGS) for genomic profiling.
- Evaluation of objective response rate (ORR) to various systemic therapies.
Main Results:
- Most FH-RCC cases (82%) resulted from germline FH variants; however, a significant portion (16%) had biallelic somatic FH loss.
- NF2 mutations were the most frequent co-occurring alteration (n=5).
- FH-RCC exhibited a lower mutation count but a higher fraction of the genome altered compared to clear-cell RCC.
- Combination mTOR/VEGF therapy achieved an ORR of 44% (18 patients), VEGF monotherapy 20% (15 patients), and checkpoint inhibitors or mTOR monotherapy 0% (8 and 4 patients, respectively). No complete responses were observed.
Conclusions:
- FH-RCC can arise from germline or somatic FH alterations, sharing similar molecular features including NF2 mutations, low tumor mutational burden, and high fraction of genome altered.
- While immunotherapy alone showed no objective responses, combination mTOR/VEGF therapy demonstrated encouraging efficacy in metastatic FH-RCC.
- Further research is warranted to optimize systemic treatment strategies for this rare and aggressive cancer.
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