FH缺陷型肾细胞癌的综合分子谱分析确定了分子亚型和潜在治疗靶点。

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

作者信息

Zhang Xingming, Zhao Junjie, Yin Xiaoxue, Liang Jiayu, Wang Yongquan, Zheng Linmao, Tan Ping, Lin Yifei, Xu Nanwei, Zhu Sha, Chen Junru, Zhao Jinge, Hu Xu, Pan Xiuyi, Nie Ling, Zhang Mengni, Chen Yuntian, Zhang Yaowen, Liu Haoyang, Dai Jindong, Wang Zhipeng, Liu Haolin, Ni Yuchao, Rupp Niels J, Moch Holger, Sheng Xinan, Gong Kan, Liu Xiaodong, Chen Zhibin, He Zhengyu, Wang Yaodong, Xu Lijing, Liu Mingsheng, Zhou Hongqing, Tang Bo, Huang Rui, Wei Qiang, Li Xiang, Liu Jiyan, Yao Jin, Liao Banghua, Liu Zhenhua, Shen Pengfei, Chen Ni, Zeng Hao, Sun Guangxi

机构信息

Department of Urology, Institute of Urology, Sichuan Clinical Research Center for kidney and urologic diseases, West China Hospital, Sichuan University, Chengdu, China.

Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.

出版信息

Nat Commun. 2025 May 12;16(1):4398. doi: 10.1038/s41467-025-59513-8.

DOI:10.1038/s41467-025-59513-8

PMID:40355427

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12069531/

Abstract

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare yet highly lethal kidney cancer. To deepen our understanding of FH-deficient RCC, we conduct a comprehensive integrated genomic study. We analyze the association of FH alteration patterns with tumor heterogeneity and develop a CpG site-specific methylation signature for precise identification of FH-deficient RCC. Transcriptomic analysis unveils three distinctive molecular subtypes characterized by enrichment of immune/Angiogenic/Stromal (C1), WNT/Notch/MAPK (C2), and proliferation/stemness (C3) pathways, respectively. Tumors in C1 derive the most substantial survival benefit from a combination of immune checkpoint blockade (ICB) and anti-angiogenic therapy. Tumors in C2 display moderate response to this therapeutic approach. In contrast, tumors in C3 exhibit an unfavorable response to anti-angiogenic monotherapy and its combination with ICB. These findings contribute to a profound understanding of the aggressive nature of FH-deficient RCC, offering insights into potential precision medicine approaches for disease management.

摘要

富马酸水合酶缺陷型肾细胞癌（FH缺陷型RCC）是一种罕见但极具致命性的肾癌。为了加深我们对FH缺陷型RCC的理解，我们开展了一项全面的综合基因组研究。我们分析了FH改变模式与肿瘤异质性的关联，并开发了一种CpG位点特异性甲基化特征，用于精确识别FH缺陷型RCC。转录组分析揭示了三种不同的分子亚型，分别以免疫/血管生成/基质（C1）、WNT/Notch/MAPK（C2）和增殖/干性（C3）途径的富集为特征。C1亚型的肿瘤从免疫检查点阻断（ICB）和抗血管生成治疗的联合应用中获得最大的生存益处。C2亚型的肿瘤对这种治疗方法表现出中度反应。相比之下，C3亚型的肿瘤对抗血管生成单药治疗及其与ICB的联合治疗表现出不良反应。这些发现有助于深入了解FH缺陷型RCC的侵袭性本质，为疾病管理的潜在精准医学方法提供见解。