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

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. Overall design: To comprehensively explore the molecular landscape and biological subtypes of FH-deficient RCC, offering insights for novel therapies, we performed RNA-seq on primary tumors of FH-deficient RCC from 56 patients and 37 paired adjacent normal kidney tissues to conduct gene expression profiling analysis.