Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, CB2 0XZ, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK.
Nat Commun. 2022 Mar 17;13(1):1407. doi: 10.1038/s41467-022-28237-4.
Barrett's esophagus is a pre-malignant lesion that can progress to esophageal adenocarcinoma. We perform a multi-omic analysis of pre-cancer samples from 146 patients with a range of outcomes, comprising 642 person years of follow-up. Whole genome sequencing reveals complex structural variants and LINE-1 retrotransposons, as well as known copy number changes, occurring even prior to dysplasia. The structural variant burden captures the most variance across the cohort and genomic profiles do not always match consensus clinical pathology dysplasia grades. Increasing structural variant burden is associated with: high levels of chromothripsis and breakage-fusion-bridge events; increased expression of genes related to cell cycle checkpoint, DNA repair and chromosomal instability; and epigenetic silencing of Wnt signalling and cell cycle genes. Timing analysis reveals molecular events triggering genomic instability with more clonal expansion in dysplastic samples. Overall genomic complexity occurs early in the Barrett's natural history and may inform the potential for cancer beyond the clinically discernible phenotype.
巴雷特食管是一种癌前病变，可进展为食管腺癌。我们对 146 名患者的癌前样本进行了多组学分析，这些患者的预后各不相同，随访时间范围为 642 人年。全基因组测序揭示了复杂的结构变异和 LINE-1 反转录转座子，以及已知的拷贝数变化，甚至在不典型增生之前就已经发生。结构变异负担在整个队列中捕获了最大的变异性，基因组图谱并不总是与共识临床病理学不典型增生分级相匹配。结构变异负担的增加与：高水平的染色体重排和断裂-融合-桥事件；与细胞周期检查点、DNA 修复和染色体不稳定性相关的基因表达增加；以及 Wnt 信号和细胞周期基因的表观遗传沉默有关。时间分析揭示了触发基因组不稳定性的分子事件，在不典型增生样本中具有更多的克隆扩增。总体基因组复杂性在巴雷特食管的自然史早期发生，可能为临床可识别表型之外的癌症提供潜在信息。
