| Popis: |
Extrachromosomal circular DNA is a newly evolved hallmark in cancer and is associated with cancer genome instability, oncogene amplification, acquired resistance, and disease progression. A Cancer Circular Genome Atlas (CCGA) consortium is formed to map the missing link of circulome in cancers. Here, we report our pilot CCGA results which we comprehensively characterize the chromosomal DNA, extrachromosomal circular DNA, and transcriptomic alteration landscape in urothelial bladder carcinoma (UBC) of 80 patients by whole-genome/exon sequencing, Circle-seq, single-molecule long-read sequencing technology, and RNA sequencing. Leveraging these large amounts of pair-wise (UBC vs. normal adjacent tissue) and trans-OMICS (genome, circulome, transcriptome) data, we exploit the genome-wide landscape of circular DNA-associated somatic mutations, unbalanced structural variations, oncogene amplification, genomic distributions, structure, and correlations with altered gene expression and clinical outcomes in UBCs. Our results reveal that UBCs contain high load of extrachromosomal circular DNAs which are in cis correlated with cluster of hypermutations (kataegis), copy number variations, oncogene amplifications, structure variations, DNA repair alteration, as well as poor clinical survival. Furthermore, our analyses probe high frequency (81%) of chromothripsis-like events in UBCs, supported by the detection of an extremely chimeric circular DNA containing DNA fragments from nine chromosomes. The CCGA-UBC presents an integrative trans-OMICS analysis strategy to map landscape of extrachromosomal circular DNAs in cancers and may provide opportunities for the development of novel therapeutic strategies. |
