Lars Bolund Institute of Regenerative Medicine, HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
College of Life Sciences, University of Chinese Academy of Science, Beijing 100049, China.
Theranostics. 2024 Aug 19;14(13):5102-5122. doi: 10.7150/thno.99563. eCollection 2024.
Extrachromosomal circular DNA is a hallmark of cancer, but its role in shaping the genome heterogeneity of urothelial bladder carcinoma (UBC) remains poorly understood. Here, we comprehensively analyzed the features of extrachromosomal circular DNA in 80 UBC patients. We performed whole-genome/exome sequencing (WGS/WES), Circle-Seq, single-molecule real-time (SMRT) long-read sequencing of circular DNA, and RNA sequencing (RNA-Seq) on 80 pairs of tumor and AT samples. We used our newly developed circular DNA analysis software, Circle-Map to detect small extrachromosomal circular DNA from Circle-Seq data. We observed a high load and significant heterogeneity of extrachromosomal circular DNAs in UBC, including numerous single-locus and complex chimeric circular DNAs originating from different chromosomes. This includes highly chimeric circular DNAs carrying seven oncogenes and circles from nine chromosomes. We also found that large tumor-specific extrachromosomal circular DNAs could influence genome-wide gene expression, and are detectable in time-matched urinary sediments. Additionally, we found that the extrachromosomal circular DNA correlates with hypermutation, copy number variation, oncogene amplification, and clinical outcome. Overall, our study provides a comprehensive extrachromosomal circular DNA map of UBC, along with valuable data resources and bioinformatics tools for future cancer and extrachromosomal circular DNA research.
染色体外环状 DNA 是癌症的一个标志，但它在塑造尿路上皮膀胱癌 (UBC) 基因组异质性方面的作用仍知之甚少。在这里，我们全面分析了 80 例 UBC 患者中染色体外环状 DNA 的特征。我们对 80 对肿瘤和 AT 样本进行了全基因组/外显子组测序 (WGS/WES)、环状 DNA 的 Circle-Seq、单分子实时 (SMRT) 长读测序和 RNA 测序 (RNA-Seq)。我们使用我们新开发的环状 DNA 分析软件 Circle-Map 从 Circle-Seq 数据中检测小染色体外环状 DNA。我们观察到 UBC 中染色体外环状 DNA 的高负荷和显著异质性，包括来自不同染色体的许多单基因座和复杂嵌合环状 DNA。这包括携带七个癌基因的高度嵌合环状 DNA 和来自九个染色体的环状 DNA。我们还发现，大肿瘤特异性染色体外环状 DNA 可以影响全基因组基因表达，并可在时间匹配的尿沉渣中检测到。此外，我们发现染色体外环状 DNA 与超突变、拷贝数变异、癌基因扩增和临床结果相关。总的来说，我们的研究提供了 UBC 的全面染色体外环状 DNA 图谱，以及未来癌症和染色体外环状 DNA 研究的有价值的数据资源和生物信息学工具。
