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. 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.

本研究深入探究延胡索酸水合酶（Fumarate Hydratase, FH）缺陷型肾细胞癌（renal cell carcinoma, RCC）的多组学图谱，旨在阐明这种罕见且极具侵袭性的肾细胞癌背后的复杂分子机制。本研究分析了126例FH缺陷型肾细胞癌患者，明确了FH基因独特的变异谱，其中截短突变与不良预后因素及免疫检查点阻断治疗应答不佳显著相关。本研究鉴定出三种具有不同临床/基因组特征、全身治疗应答各异的分子亚型，进一步深化了对FH缺陷型肾细胞癌异质性肿瘤微环境（尤其是免疫相关微环境）的认知，并提出了潜在治疗靶点。上述研究结果可为分子分型提供依据，为优化FH缺陷型肾细胞癌的个体化治疗策略、提升治疗应答率指明了方向。为全面解析FH缺陷型肾细胞癌的分子图谱与生物学亚型，为新型治疗方案提供理论支撑，本研究对56例FH缺陷型肾细胞癌患者的原发肿瘤组织及37例配对癌旁正常肾组织开展了RNA测序（RNA-seq），并完成基因表达谱分析。