ArticleCancer discovery2023
FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer.
Article in Cancer discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 71 citations in OpenAlex.
- Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.bioRxiv : the preprint server for biology · 2026Article
- Dynamic control of nucleotide metabolism in physiology and disease.Nature cell biology · 2026Review
- Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.Nature metabolism · 2026Article
- Biochemical characterization of the FH variant p.Lys414Glu reveals loss of enzymatic function and disrupted multimerization.Molecular genetics and metabolism reports · 2026Article
- Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids.Acta pharmacologica Sinica · 2026Article
- Probing intratumoral metabolic compartmentalisation in a patient with fumarate hydratase-deficient renal cancer using clinical hyperpolarisedCommunications medicine · 2026Article
- Hereditary leiomyomatosis and renal cell carcinoma: a case report and literature review.Frontiers in urology · 2026Article
- Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.Nature metabolism · 2025Article
- Purine metabolism: a pan-cancer metabolic dysregulation across circulation and tissues.Molecular cancer · 2025Article
- Genetic correlates of malignancy in TFE3-rearranged PEComa: a series of 14 cases.Histopathology · 2025Article
- High tide or low tide: the transport and metabolism of mitochondrial nucleotides.The Biochemical journal · 2025Review
- Targeting metabolic and epigenetic reprogramming in metastatic fumarate hydratase-deficient renal cell carcinoma.Clinical & experimental metastasis · 2025Review
- Prioritizing disease-associated missense variants with chemoproteomic-detected amino acids.American journal of human genetics · 2025Article
- Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.Genes & development · 2025Article
- Comprehensive molecular profiling of FH-deficient renal cell carcinoma identifies molecular subtypes and potential therapeutic targets.Nature communications · 2025Article
- Metabolic reprogramming in cancer and senescence.MedComm · 2025Review
- Exploration of the mutational landscape of cutaneous leiomyoma confirms FH as a driver gene and identifies targeting purine metabolism as a potential therapeutic strategy.The British journal of dermatology · 2025Article
- Addressing genome scale design tradeoffs in Pseudomonas putida for bioconversion of an aromatic carbon source.NPJ systems biology and applications · 2025Article
- Emerging roles of metabolic biomarkers in renal cell carcinoma: from molecular mechanisms to clinical implications.Frontiers in cell and developmental biology · 2025Review
- Complete response to fifth-line anti-PD-1 rechallenge in fumarate hydratase-mutated papillary renal cell carcinoma.NPJ precision oncology · 2024Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors. SIGNIFICANCE: This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers. This article is featured in Selected Articles from This Issue, p. 1949.
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Registered trials
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