乳腺导管原位癌又称零期乳腺癌，属于最早期的乳腺癌，大部分患者仅需接受小手术简单切除，术后即使不接受放化疗或内分泌治疗，也不会复发或恶化为乳腺浸润癌，少数患者术后数年甚至数十年仍然可能复发或恶化，需要积极治疗、密切随访。了解乳腺导管原位癌复发恶化前的基因组变化，有助于确定哪些患者将来复发恶化风险较高或较低，以避免治疗不足或过度。不过，对于数年甚至数十年前福尔马林固定石蜡包埋的肿瘤组织，目前仍然难以进行基因组分析。 2023年8月15日，全球自然科学三大旗舰期刊之一、美国《细胞》正刊在线发表美国德克萨斯大学MD安德森癌症中心、杜克大学医学院、贝勒医学院、英国伦敦大学国王学院盖伊癌症中心、英国癌症研究基金会、荷兰癌症研究院、范列文虎克医院、荷兰癌症基金会、莱顿大学医学中心的研究报告，利用一种新方法可以对数年甚至数十年前福尔马林固定石蜡包埋的肿瘤组织成千上万个细胞进行DNA测序。 该研究通过分析4万330个单细胞对该方法进行验证，这些细胞来自细胞系、冷冻组织以及已经储存3～31年的23个乳腺肿瘤福尔马林固定石蜡包埋标本。 对10例患者的乳腺导管原位癌及其2～16年后复发癌分析表明，许多原发的乳腺导管原位癌已经存在全基因组倍增和克隆多样化，并且与复发癌的持续亚克隆基因组谱系相同。 进化分析表明，该队列大多数乳腺导管原位癌病例经历了进化瓶颈，并进一步确定了复发相关持续亚克隆的染色体畸变。 因此，该研究结果表明，该方法可以对存档福尔马林固定石蜡包埋的成千上万个细胞进行大规模单细胞DNA并行测序，开辟了对世界各地收集和存档的大量临床福尔马林固定石蜡包埋组织进行研究的新途径，可用于研究癌症和其他人类疾病的长期临床结局数据。此外，该方法还可以对未固定的组织（新鲜或冷冻）进行大规模单细胞DNA并行测序，并对许多现有单细胞DNA并行测序方法进行基准测试，从而提高数据质量。最重要的是，该研究发现乳腺导管原位癌复发或浸润前几年甚至十几年就已存在某些基因组变化，有助于确定哪些患者将来复发恶化风险较高或较低，以避免治疗不足或治疗过度，故有必要进一步开展大样本临床研究进行验证。Cell. 2023 Aug 15. IF: 64.5Archival single-cell genomics reveals persistent subclones during DCIS progression.Kaile Wang, Tapsi Kumar, Junke Wang, Darlan Conterno Minussi, Emi Sei, Jianzhuo Li, Tuan M. Tran, Aatish Thennavan, Min Hu, Anna K. Casasent, Zhenna Xiao, Shanshan Bai, Lei Yang, Lorraine M. King, Vandna Shah, Petra Kristel, Carolien L. van der Borden, Jeffrey R. Marks, Yuehui Zhao, Amado J. Zurita, Ana Aparicio, Brian Chapin, Jie Ye, Jianjun Zhang, Don L. Gibbons, Grand Challenge PRECISION Consortium, Ellinor Sawyer, Alastair M. Thompson, Andrew Futreal, E. Shelley Hwang, Jelle Wesseling, Esther H. Lips, Nicholas E. Navin.UT MD Anderson Cancer Center, Houston, TX, USA; MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA; Duke University School of Medicine, Durham, NC, USA; Baylor College of Medicine, Houston, TX, USA; Guy's Cancer Centre, King's College London, London, UK; Grand Challenge PRECISION Consortium, Cancer Research UK; Netherlands Cancer Institute, Amsterdam, the Netherlands; KWF Dutch Cancer Foundation; Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Leiden University Medical Center, Leiden, the Netherlands.- Arc-well is a high-throughput single-cell DNA-seq method for archival FFPE tissues
- Arc-well reliably profiled thousands of cells from 27 FFPE tissues archived for years
- Persistent subclones from DCIS and matched recurrences were identified
- Most DCIS cases in this cohort underwent an evolutionary bottleneck
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.KEYWORDS: Arc-well, single-cell DNA sequencing, FFPE material, archival samples, ductal carcinoma in situ recurrence, tumor evolution, breast cancer, premalignanciesDOI: 10.1016/j.cell.2023.07.024
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