小柯机器人

加拿大英属哥伦比亚大学Alexander W. Wyatt团队近期取得重要工作进展，他们最新研究开发了治疗耐药前列腺癌的深层全基因组ctDNA年表。该项研究成果2022年7月20日在线出版于《自然》杂志上。

在这里，研究人员对侵袭性前列腺癌患者的系列血浆和同步转移进行深度全基因组测序。他们全面评估了所有类别的基因组改变，并表明ctDNA包含多个优势种群，其进化历史经常表明全基因组加倍和突变过程的转变。尽管组织和ctDNA显示出一致的克隆扩展癌症驱动改变，但大多数个体转移仅占总ctDNA的一小部分。通过比较雄激素受体（AR）通路强效抑制剂临床进展前后的连续 ctDNA，研究人员揭示了群体重组仅集中在AR增强作为获得性治疗耐药的主要基因组驱动因素。

最后，研究人员利用ctDNA中的核小体足迹来推断同步活检转移灶中的mRNA表达，包括治疗诱导的AR转录因子信号传导活性的变化。他们的结果提供了对癌症生物学的见解，并表明液体活检可以用作全面的多组学发现的工具。

据了解，血浆循环肿瘤DNA（ctDNA）是临床肿瘤基因分型和纵向疾病监测的新工具。然而，然而，由于过去强调定向和低分辨率的分析方法，研究人员对构成大宗ctDNA的不同群体的理解并不完整。

附：英文原文

Title: Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

Author: Herberts, Cameron, Annala, Matti, Sipola, Joonatan, Ng, Sarah W. S., Chen, Xinyi E., Nurminen, Anssi, Korhonen, Olga V., Munzur, Asl D., Beja, Kevin, Schnlau, Elena, Bernales, Cecily Q., Ritch, Elie, Bacon, Jack V. W., Lack, Nathan A., Nykter, Matti, Aggarwal, Rahul, Small, Eric J., Gleave, Martin E., Quigley, David A., Feng, Felix Y., Chi, Kim N., Wyatt, Alexander W.

Issue&Volume: 2022-07-20

Abstract: Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2,3,4,5,6,7,8,9,10,11,12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.

DOI: 10.1038/s41586-022-04975-9

Source: https://www.nature.com/articles/s41586-022-04975-9

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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