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

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: GSE273036 | GEO | 2024/10/20

REPOSITORIES: GEO

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Distinct succinate modifying products are clinically diagnostic and prognostic biomarkers for fumarate hydratase deficient renal cell carcinoma

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| PRJNA533711 | ENA

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Project description:The development of molecularly targeted therapies builds upon the identification of tumor clades with shared molecular abnormalities. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial syndrome resulting from germline mutation of the two-hit tumor suppressor gene, Fumarate Hydratase (FH). HLRCC renal tumors present often in young adults, exhibit unique histological features and are particularly aggressive. HLRCC is uncommon and poorly understood, and whether there are sporadic renal tumors with similar characteristics, is unclear. Notably, FH can also be inactivated somatically in RCC, and should be included among FH-deficient (FHD) kidney tumors. We identified a tumor clade without FH mutations but with similar morphological and molecular characteristics as well as aggressive clinical behavior, which we name FHDL (FHD-like). We show that FHD/FHDL tumors represent a unique subtype of CIMP (CpG Island Methylator Phenotype) with the highest levels of overall genome methylation and CDKN2A silencing. FHD/FHDL tumors are characterized by convergent activation of the Hippo pathway as determined by frequent and mutually exclusive mutations in NF2 and PTPN14. AKR1B10, an NRF2 target, was upregulated in FHD/FHDL tumors as well as GATA3, which suggests a shared origin in the renal medulla and is consistent with topological studies. There is loss of 5-hydroxymethylcytosine in both FHD and FHDL tumors. These data define a group of particularly aggressive renal cancers with shared molecular features and potential targets for therapeutic intervention.

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