Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
Genome Biol. 2020 Jul 6;21(1):162. doi: 10.1186/s13059-020-02045-9.
Investigating genome evolution in response to therapy is difficult in human tissue samples. To address this challenge, we develop an unbiased whole-genome plasma DNA sequencing approach that concurrently measures genomic copy number and exome mutations from archival cryostored plasma samples. This approach is applied to study longitudinal blood plasma samples from prostate cancer patients, where longitudinal tissue biopsies from the bone and other metastatic sites have been challenging to collect.
A molecular characterization of archival plasma DNA from 233 patients and genomic profiling of 101 patients identifies clinical correlations of aneuploid plasma DNA profiles with poor survival, increased plasma DNA concentrations, and lower plasma DNA size distributions. Deep-exome sequencing and genomic copy number profiling are performed on 23 patients, including 9 patients with matched metastatic tissues and 12 patients with serial plasma samples. These data show a high concordance in genomic alterations between the plasma DNA and metastatic tissue samples, suggesting the plasma DNA is highly representative of the tissue alterations. Longitudinal sequencing of 12 patients with 2-5 serial plasma samples reveals clonal dynamics and genome evolution in response to hormonal and chemotherapy. By performing an integrated evolutionary analysis, minor subclones are identified in 9 patients that expanded in response to therapy and harbored mutations associated with resistance.
This study provides an unbiased evolutionary approach to non-invasively delineate clonal dynamics and identify clones with mutations associated with resistance in prostate cancer.
在人类组织样本中研究治疗反应引起的基因组进化较为困难。为了解决这一挑战，我们开发了一种无偏的全基因组血浆 DNA 测序方法，该方法可以同时从存档的冷冻血浆样本中测量基因组拷贝数和外显子突变。我们应用该方法研究了前列腺癌患者的纵向血浆样本，在这些患者中，从骨和其他转移部位采集纵向组织活检一直具有挑战性。
对 233 名患者的存档血浆 DNA 进行分子特征分析和 101 名患者的基因组分析，确定了非整倍体血浆 DNA 谱与不良生存、血浆 DNA 浓度增加和血浆 DNA 大小分布降低相关的临床相关性。对 23 名患者进行了深度外显子测序和基因组拷贝数分析，其中包括 9 名具有匹配转移性组织的患者和 12 名具有连续血浆样本的患者。这些数据表明，血浆 DNA 和转移性组织样本中的基因组改变高度一致，表明血浆 DNA 高度代表了组织改变。对 12 名具有 2-5 个连续血浆样本的患者进行纵向测序，揭示了激素和化疗治疗下的克隆动力学和基因组进化。通过进行综合进化分析，在 9 名患者中鉴定出了在治疗中扩增并携带耐药相关突变的次要亚克隆。
本研究提供了一种非侵入性的进化方法，用于描绘前列腺癌中的克隆动力学，并鉴定出与耐药相关的突变克隆。
