导管内癌（DCIS）是浸润性乳腺癌常见的前体病变。对其基因组在复发疾病中的发展认识不足，部分原因是由于甲醛固定石蜡包埋（FFPE）样本的基因组分析面临的挑战。在此，我们开发了一种高通量单细胞DNA测序方法Arc-well，该方法可与FFPE样本兼容。通过对细胞系、冷冻组织和存放3-31年的27个乳腺、肺和前列腺肿瘤FFPE样本的40,330个单细胞进行分析，我们验证了我们的方法。对10个DCIS和复发疾病术后2-16年的匹配患者的分析结果显示，许多原发性DCIS已经经历了全基因组倍增和克隆分叉，并且它们与复发病变中的持续亚克隆共享基因组谱系。演化分析表明，我们研究中的大多数DCIS病例经历了演化瓶颈，并进一步确认了与复发相关的持续亚克隆中的染色体异常。版权所有© 2023 Elsevier Inc. 保留所有权利。

Ductal carcinoma in situ (DCIS) is a common precursor of invasive breast cancer. Our understanding of its genomic progression to recurrent disease remains poor, partly due to challenges associated with the genomic profiling of formalin-fixed paraffin-embedded (FFPE) materials. Here, we developed Arc-well, a high-throughput single-cell DNA-sequencing method that is compatible with FFPE materials. We validated our method by profiling 40,330 single cells from cell lines, a frozen tissue, and 27 FFPE samples from breast, lung, and prostate tumors stored for 3-31 years. Analysis of 10 patients with matched DCIS and cancers that recurred 2-16 years later show that many primary DCIS had already undergone whole-genome doubling and clonal diversification and that they shared genomic lineages with persistent subclones in the recurrences. Evolutionary analysis suggests that most DCIS cases in our cohort underwent an evolutionary bottleneck, and further identified chromosome aberrations in the persistent subclones that were associated with recurrence.Copyright © 2023 Elsevier Inc. All rights reserved.