
Rationale: 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. Methods: 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. Results: 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. Conclusions: 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.
Male, Mutation/genetics, DNA Copy Number Variations, Whole Genome Sequencing, Urinary Bladder Neoplasms/genetics, DNA Copy Number Variations/genetics, Exome Sequencing/methods, Genetic Heterogeneity, Urinary Bladder Neoplasms, Whole Genome Sequencing/methods, Exome Sequencing, Mutation, DNA, Circular/genetics, Humans, Female, DNA, Circular, Research Paper, Aged
Male, Mutation/genetics, DNA Copy Number Variations, Whole Genome Sequencing, Urinary Bladder Neoplasms/genetics, DNA Copy Number Variations/genetics, Exome Sequencing/methods, Genetic Heterogeneity, Urinary Bladder Neoplasms, Whole Genome Sequencing/methods, Exome Sequencing, Mutation, DNA, Circular/genetics, Humans, Female, DNA, Circular, Research Paper, Aged
| selected citations These citations are derived from selected sources. This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically). | 14 | |
| popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network. | Top 10% | |
| influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically). | Average | |
| impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network. | Top 10% |
