In cancer, extrachromosomal circular DNA (ecDNA), or megabase-pair amplified circular DNA, plays an essential role in intercellular heterogeneity and tumor cell revolution because of its non-Mendelian inheritance. We developed circlehunter (https://github.com/suda-huanglab/circlehunter), a tool for identifying ecDNA from ATAC-Seq data using the enhanced chromatin accessibility of ecDNA. Using simulated data, we showed that circlehunter has an F1 score of 0.93 at 30× local depth and read lengths as short as 35 bp. Based on 1312 ecDNAs predicted from 94 publicly available datasets of ATAC-Seq assays, we found 37 oncogenes contained in these ecDNAs with amplification characteristics. In small cell lung cancer cell lines, ecDNA containing MYC leads to amplification of MYC and cis-regulates the expression of NEUROD1, resulting in an expression pattern consistent with the NEUROD1 high expression subtype and sensitive to Aurora kinase inhibitors. This showcases that circlehunter could serve as a valuable pipeline for the investigation of tumorigenesis.

在癌症中，染色体外环状 DNA (ecDNA) 或兆碱基对扩增环状 DNA 由于其非孟德尔遗传，在细胞间异质性和肿瘤细胞革命中起着至关重要的作用。我们开发了 circlehunter (https://github.com/suda-huanglab/circlehunter)，这是一种使用增强的 ecDNA 染色质可及性从 ATAC-Seq 数据中识别 ecDNA 的工具。使用模拟数据，我们发现 circlehunter 在 30× 局部深度和短至 35 bp 的读取长度下的 F1 得分为 0.93。基于从 94 个公开可用的 ATAC-Seq 分析数据集中预测的 1312 个 ecDNA，我们发现这些 ecDNA 中包含 37 个具有扩增特征的致癌基因。在小细胞肺癌细胞系中，含有MYC 的ecDNA 导致MYC扩增并顺式调节NEUROD1的表达，导致表达模式与NEUROD1高表达亚型一致并对极光激酶抑制剂敏感。这表明 circlehunter 可以作为研究肿瘤发生的有价值的管道。