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兴工具，由于过去强调有针对性和低分辨率的分析方法，我们对构成ctDNA批量的不同群体的了解是不完整的，本研究对侵袭性前列腺癌患者的连续血浆和同步转移进行深度全基因组测序。

研究人员对33例侵袭性前列腺癌患者的61份血浆cfDNA样本和匹配的转移性组织样本进行深度全基因组测序。

研究人员发现，具有高ctDNA组分的样本可以解剖转移性癌症的进化历史、亚克隆的时间进化动力学，并发现治疗耐药性的基因组和转录组机制。这种分辨率以前只能通过侵袭性和重复性的新鲜组织活检来实现。ctDNA的全基因组测序提供了大量关于扩散到全身不同转移灶的信息。利用新开发的计算机程序，研究人员可以精确地查明患者体内各种癌症的独特基因构成，从而对疾病有了更全面的了解。

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.

原文链接

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

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