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

Xingming Zhang, Junjie Zhao, Xiaoxue Yin, Jiayu Liang, Yongquan Wang, Linmao Zheng, Ping Tan, Yifei Lin, Nanwei Xu, Sha Zhu, Junru Chen, Jinge Zhao, Xu Hu, Xiuyi Pan, Ling Nie, Mengni Zhang, Yuntian Chen, Yaowen Zhang, Haoyang Liu, Jindong Dai, Zhipeng Wang, Haolin Liu, Yuchao Ni, Niels J. Rupp, Holger Moch, Xinan Sheng, Kan Gong, Xiaodong Liu, Zhibin Chen, Zhengyu He, Yaodong Wang, Lijing Xu, Mingsheng Liu, Hongqing Zhou, Bo Tang, Rui Huang, Qiang Wei, Xiang Li, Jiyan Liu, Jin Yao, Banghua Liao, Zhenhua Liu, Pengfei Shen (), Ni Chen (), Hao Zeng () and Guangxi Sun ()
Additional contact information
Xingming Zhang: Sichuan University
Junjie Zhao: Sichuan University
Xiaoxue Yin: Sichuan University
Jiayu Liang: Sichuan University
Yongquan Wang: Army Medical University
Linmao Zheng: Sichuan University
Ping Tan: Sichuan University
Yifei Lin: Sichuan University
Nanwei Xu: Sichuan University
Sha Zhu: Sichuan University
Junru Chen: Sichuan University
Jinge Zhao: Sichuan University
Xu Hu: Sichuan University
Xiuyi Pan: Sichuan University
Ling Nie: Sichuan University
Mengni Zhang: Sichuan University
Yuntian Chen: Sichuan University
Yaowen Zhang: Sichuan University
Haoyang Liu: Sichuan University
Jindong Dai: Sichuan University
Zhipeng Wang: Sichuan University
Haolin Liu: Sichuan University
Yuchao Ni: Sichuan University
Niels J. Rupp: University Hospital Zurich
Holger Moch: University Hospital Zurich
Xinan Sheng: Peking University Cancer Hospital and Institute
Kan Gong: Peking University First Hospital
Xiaodong Liu: The First Affiliated Hospital of Kunming Medical University
Zhibin Chen: The First People’s Hospital of Neijiang
Zhengyu He: Yaan People’s Hospital
Yaodong Wang: Mianyang Central Hospital
Lijing Xu: Sichuan University
Mingsheng Liu: Affiliated Qujing Hospital of Kunming Medical University
Hongqing Zhou: Affiliated Qujing Hospital of Kunming Medical University
Bo Tang: Sichuan University
Rui Huang: Sichuan University
Qiang Wei: Sichuan University
Xiang Li: Sichuan University
Jiyan Liu: Sichuan University
Jin Yao: Army Medical University
Banghua Liao: Sichuan University
Zhenhua Liu: Sichuan University
Pengfei Shen: Sichuan University
Ni Chen: Sichuan University
Hao Zeng: Sichuan University
Guangxi Sun: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59513-8

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