巴雷特氏食道癌变中的染色体外DNA

SCI 20 May 2023

Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus

(Nature IF: 49.96)

Luebeck J, Ng AWT, Galipeau PC, Li X, Sanchez CA, Katz-Summercorn AC, Kim H, Jammula S, He Y, Lippman SM, Verhaak RGW, Maley CC, Alexandrov LB, Reid BJ, Fitzgerald RC, Paulson TG, Chang HY, Wu S, Bafna V, Mischel PS. Extrachromosomal DNA in the cancerous transformation of Barrett's oesophagus. Nature. 2023 Apr;616(7958):798-805. doi: 10.1038/s41586-023-05937-5. Epub 2023 Apr 12. PMID: 37046089; PMCID: PMC10132967.

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 ademocarcinoma (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.

染色体外DNA（ecDNA）上的肿瘤基因扩增推动了肿瘤的演变和对治疗的抵抗，并与癌症患者的不良后果有关。目前，还不清楚ecDNA是否是基因组不稳定的后期表现，或者它是否可以成为从发育不良到癌症过渡的早期事件。在此，为了更好地了解ecDNA的发展，我们分析了食道腺癌（EAC）或巴雷特食道患者的全基因组测序（WGS）数据。这些数据包括剑桥大学巴雷特氏食道监测和EAC队列中的206份活检报告。我们还分析了WGS和组织学数据，这些数据来自弗雷德-哈钦森癌症中心一项病例对照研究中80名患者在2个时间点收集的多个区域的活检。在剑桥大学的队列中，ecDNA的频率在巴雷特-食道相关的早期阶段（24%）和晚期阶段（43%）EAC之间有所增加，这表明ecDNA是在癌症发展过程中形成的。在弗雷德-哈钦森癌症中心的队列中，33%的EAC患者在诊断EAC前或诊断时至少有一次食道活检有ecDNA。在癌症诊断前收集的活检中，后来发展为EAC的患者的样本中的ecDNA水平高于未发展为EAC的患者的样本。我们发现，ecDNAs包含不同的致癌基因和免疫调节基因集合。此外，在疾病的晚期，ecDNA的拷贝数和结构的复杂性都有所增加。我们的研究结果表明，ecDNA可以在从高级别发育不良到癌症的早期发展，并且ecDNA在正向选择下逐步形成和进化。

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