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

Author

Listed:
  • 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
    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
    University of Zurich)

  • Holger Moch

    (University Hospital Zurich
    University of 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)

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.

Suggested Citation

  • 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 Z, 2025. "Comprehensive molecular profiling of FH-deficient renal cell carcinoma identifies molecular subtypes and potential therapeutic targets," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59513-8
    DOI: 10.1038/s41467-025-59513-8
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