Integrated molecular characterization of fumarate hydratase deficient renal cell carcinoma

Guangxi Sun, Xingming Zhang, Jiayu Liang, Xiuyi Pan, Sha Zhu, Zhenhua Liu, Cameron M. Armstrong, Jianhui Chen, Wei Lin, Banghua Liao, Tianhai Lin, Rui Huang, Mengni Zhang, Linmao Zheng, Xiaoxue Yin, Ling Nie, Pengfei Shen, Jinge Zhao, Haoran Zhang, Jindong DaiYali Shen, Zhiping Li, Jiyan Liu, Junru Chen, Jiandong Liu, Zhipeng Wang, Xudong Zhu, Yuchao Ni, Dan Qin, Ling Yang, Yuntian Chen, Qiang Wei, Xiang Li, Qiao Zhou, Haojie Huang, Jin Yao, Ni Chen, Hao Zeng

Research output: Contribution to journalArticlepeer-review


Purpose: Fumarate hydratase deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC. Experimental Design: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FHdeficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded. Results: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03). Conclusions: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FHdeficient RCC.

Original languageEnglish (US)
Pages (from-to)1734-1743
Number of pages10
JournalClinical Cancer Research
Issue number6
StatePublished - Mar 2021

ASJC Scopus subject areas

  • General Medicine


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