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, Yahong 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, Guangxi Sun
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. Currently, there is limited understanding of the molecular subtypes of fumarate hydratase (FH)-deficient renal cell carcinoma (RCC). Here, the authors employ integrated genomics and transcriptomics to develop a CpG site-specific methylation signature for the identification of FH-deficient RCC, and to identify three distinct molecular subtypes for this rare but highly lethal kidney cancer.