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Genomic and transcriptomic features between primary and paired metastatic fumarate hydratase–deficient renal cell carcinoma

التفاصيل البيبلوغرافية
العنوان: Genomic and transcriptomic features between primary and paired metastatic fumarate hydratase–deficient renal cell carcinoma
المؤلفون: Jiayu Liang, Guangxi Sun, Xiuyi Pan, Mengni Zhang, Pengfei Shen, Sha Zhu, Jinge Zhao, Linmao Zheng, Junjie Zhao, Yuntian Chen, Xiaoxue Yin, Junru Chen, Xu Hu, Yuhao Zeng, Jianhui Chen, Yongquan Wang, Zhihong Liu, Jin Yao, Minggang Su, Rui Huang, Banghua Liao, Qiang Wei, Xiang Li, Qiao Zhou, Jiyan Liu, Yali Shen, Zhenhua Liu, Ni Chen, Hao Zeng, Xingming Zhang
المصدر: Genome Medicine, Vol 15, Iss 1, Pp 1-18 (2023)
بيانات النشر: BMC, 2023.
سنة النشر: 2023
المجموعة: LCC:Medicine
LCC:Genetics
مصطلحات موضوعية: Fumarate hydratase–deficient renal cell carcinoma, Whole-exome sequencing, DNA methylation, RNA-seq, Tumor evolution, Metastatic lesions, Medicine, Genetics, QH426-470
الوصف: Abstract Background Fumarate 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. Methods In 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. Results Paired 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 concurrent NF2 mutation 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. Conclusions Overall, 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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1756-994X
Relation: https://doaj.org/toc/1756-994X
DOI: 10.1186/s13073-023-01182-7
URL الوصول: https://doaj.org/article/6c8795d0b02740948debb30b7bd00337
رقم الأكسشن: edsdoj.6c8795d0b02740948debb30b7bd00337
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:1756994X
DOI:10.1186/s13073-023-01182-7