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Sun, Guangxi; Zhang, Xingming; Liang, Jiayu; Pan, Xiuyi; Zhu, Sha; Liu, Zhenhua; Armstrong, Cameron M; Chen, Jianhui; Lin, Wei; Liao, Banghua; Lin, Tianhai; Huang, Rui; Zhang, Mengni; Zheng, Linmao; Yin, Xiaoxue; Nie, Ling; Shen, Pengfei; Zhao, Jinge; Zhang, Haoran; Dai, Jindong; Shen, Yali; Li, Zhiping; Liu, Jiyan; Chen, Junru; Liu, Jiandong; Wang, Zhipeng; Zhu, Xudong; Ni, Yuchao; Qin, Dan; Yang, Ling; Chen, Yuntian; Wei, Qiang; Li, Xiang; Zhou, Qiao; Huang, Haojie; Yao, Jin; Chen, Ni; Zeng, Hao
Clinical cancer research, 03/2021, Volume: 27, Issue: 6Journal Article
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. Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded. 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; = 0.03). These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.
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