Genomic and transcriptomic features between primary and paired metastatic fumarate hydratase–deficient renal cell carcinoma
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Published:2023-05-02
Issue:1
Volume:15
Page:
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ISSN:1756-994X
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Container-title:Genome Medicine
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language:en
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Short-container-title:Genome Med
Author:
Liang Jiayu, Sun Guangxi, Pan Xiuyi, Zhang Mengni, Shen Pengfei, Zhu Sha, Zhao Jinge, Zheng Linmao, Zhao Junjie, Chen Yuntian, Yin Xiaoxue, Chen Junru, Hu Xu, Zeng Yuhao, Chen Jianhui, Wang Yongquan, Liu Zhihong, Yao Jin, Su Minggang, Huang Rui, Liao Banghua, Wei Qiang, Li Xiang, Zhou Qiao, Liu Jiyan, Shen Yali, Liu Zhenhua, Chen Ni, Zeng HaoORCID, Zhang Xingming
Abstract
AbstractBackgroundFumarate hydratase–deficient renal cell carcinoma (FH-RCC) is a rare highly aggressive subtype of kidney cancer for which the distinct genomic, transcriptomic, and evolutionary relationships between metastatic and primary lesions are still unclear.MethodsIn this study, whole-exome, RNA-seq, and DNA methylation sequencing were performed on primary-metastatic paired specimens from 19 FH-RCC cases, including 23 primary and 35 matched metastatic lesions. Phylogenetic and clonal evolutionary analyses were used to investigate the evolutionary characteristics of FH-RCC. Transcriptomic analyses, immunohistochemistry, and multiple immunofluorescence experiments were performed to identify the tumor microenvironmental features of metastatic lesions.ResultsPaired primary and metastatic lesions generally showed similar characteristics of tumor mutation burden, tumor neoantigen burden, microsatellite instability score, CNV burden, and genome instability index. Notably, we identified an FH-mutated founding MRCA (the most recent common ancestor) clone that dominated the early evolutionary trajectories in FH-RCC. Although both primary and metastatic lesions manifested high immunogenicity, metastatic lesions exhibited higher enrichment of T effector cells and immune-related chemokines, together with upregulation of PD-L1, TIGIT, and BTLA. In addition, we found that concurrentNF2mutation may be associated with bone metastasis and upregulation of cell cycle signature in metastatic lesions. Furthermore, although in FH-RCC metastatic lesions in general shared similar CpG island methylator phenotype with primary lesions, we found metastatic lesions displaying hypomethylated chemokine and immune checkpoints related genomic loci.ConclusionsOverall, our study demonstrated the genomic, epigenomic, and transcriptomic features of metastatic lesions in FH-RCC and revealed their early evolutionary trajectory. These results provided multi-omics evidence portraying the progression of FH-RCC.
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
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