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Comprehensive molecular profiling of FH-deficient renal cell carcinoma identifies molecular subtypes and novel therapeutic targets

ABSTRACT: Conducting an in-depth exploration of the multi-omics landscape of Fumarate Hydratase (FH)-deficient renal cell carcinoma (RCC), the study aimed to unravel the intricate molecular mechanisms underlying this rare and aggressive form of renal cancer. Analyzing 126 patients with FH-deficient RCC, we identified distinct variant spectrum of FH gene, with truncating mutation correlated with adverse prognostic factors and a worse response to immune checkpoint blockade. The identification of three molecular subtypes with diverse clinical/genomic characteristics and varying response to systemic treatment further enriched the understanding of the heterogeneous tumor microenvironment (particularly immune-related) in FH-deficient RCC, and suggested potential therapeutic targets. These findings offer a basis for molecular stratification, shedding light on the tailored therapeutic strategies in improving treatment response of FH-deficient RCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291073 | GEO | 2025/03/06

REPOSITORIES: GEO

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Multi-Omics Analysis and Molecular Subtypes Provide Potential Therapeutic Implications in Fumarate Hydratase-deficient Renal Cell Carcinoma

Project description:Conducting an in-depth exploration of the multi-omics landscape of Fumarate Hydratase (FH)-deficient renal cell carcinoma (RCC), the study aimed to unravel the intricate molecular mechanisms underlying this rare and aggressive form of renal cancer. Analyzing 126 patients with FH-deficient RCC, we identified distinct variant spectrum of FH gene, with truncating mutation correlated with adverse prognostic factors and a worse response to immune checkpoint blockade. The identification of three molecular subtypes with diverse clinical/genomic characteristics and varying response to systemic treatment further enriched the understanding of the heterogeneous tumor microenvironment (particularly immune-related) in FH-deficient RCC, and suggested potential therapeutic targets. These findings offer a basis for molecular stratification, shedding light on the tailored therapeutic strategies in improving treatment response of FH-deficient RCC.

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Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-Ribose Polymerase inhibitors and low-dose alkylating chemotherapy

Project description:Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we evaluated novel treatment approaches in newly generated models of FH- and SDHB-deficient RCC.

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Project description:Fumarate Hydratase (FH) is a mitochondrial enzyme that catalyses the reversible hydration of fumarate to malate in the TCA cycle. Germline mutations of FH lead to HLRCC, a cancer syndrome characterised by a highly aggressive form of renal cancer(1). Although HLRCC tumours metastasise rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas(2). How Fh1-deficient cells overcome these tumour suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR/Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of the HIRA enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss enables the activation of MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.

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Project description:<p>Germline or somatic loss-of-function of fumarate hydratase (FH) predisposes patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection, there is no effective therapy for FH-deficient RCC, a competent method for early diagnosis and for early detection of recurrent and metastatic disease is an unmet clinical need. Currently, at best, an annual MRI scan is offered, though typically, MRI is used for symptomatic patients only. Therefore, finding specific and sensitive biomarkers suitable for routine and simple screens is crucial for improving the clinical outcome of these patients. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed a large-scale study of plasma metabolomics comparing FH-deficient RCC patients to no-tumor control individuals or to wildtype FH RCC patients. Our results indicated two fumarate-derived metabolites, succinyl-adenosine and succinic-cysteine, to be outstanding plasma biomarkers for early diagnosis, with a positive predictive value of more than 90%. Furthermore, using pre-clinical and biochemical studies, we identified the enzymatic mechanisms by which these biomarkers are produced in and around the tumors. </p>

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Expression data from mouse kidney epithelial cells

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