Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA.
Bioinformatics and Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA, USA.
Nature. 2023 Apr;616(7958):798-805. doi: 10.1038/s41586-023-05937-5. Epub 2023 Apr 12.
Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.
癌基因扩增在染色体外 DNA（ecDNA）上驱动肿瘤的进化及其对治疗的耐药性，并与癌症患者的不良预后相关。目前，尚不清楚 ecDNA 是基因组不稳定性的后期表现，还是可以作为从发育异常向癌症转变的早期事件。在这里，为了更好地了解 ecDNA 的发展，我们分析了来自食管腺癌（EAC）或 Barrett 食管患者的全基因组测序（WGS）数据。这些数据包括剑桥大学 Barrett 食管监测和 EAC 队列中的 206 个活检。我们还分析了弗雷德·哈钦森癌症研究中心一项病例对照研究中 80 名患者在两个时间点从多个区域收集的 WGS 和组织学数据。在剑桥队列中，ecDNA 的频率在与 Barrett 食管相关的早期（24%）和晚期（43%）EAC 之间增加，这表明 ecDNA 是在癌症进展过程中形成的。在弗雷德·哈钦森癌症研究中心的队列中，33%的 EAC 患者在 EAC 诊断前或诊断时至少有一次 ecDNA 阳性的食管活检。在癌症诊断前收集的活检中，后来发展为 EAC 的患者的 ecDNA 水平高于未发展为 EAC 的患者。我们发现 ecDNA 包含多种致癌基因和免疫调节基因。此外，ecDNA 在疾病的更晚期表现出更高的拷贝数和结构复杂性增加。我们的研究结果表明，ecDNA 可以在从高级别发育异常向癌症转变的早期阶段发展，并且 ecDNA 在正选择下逐渐形成和进化。
