Related Experiment Video
Updated: Sep 4, 2025
Serum and Plasma Copy Number Detection Using Real-time PCR
Published on: December 15, 2017
Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer
Cameron Herberts1, Matti Annala1,2, Joonatan Sipola2
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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 incomplete2-12. 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.
Insights
Deep sequencing of circulating tumor DNA (ctDNA) in aggressive prostate cancer reveals diverse tumor populations and identifies androgen receptor (AR) augmentation as a key driver of treatment resistance. This liquid biopsy approach enables comprehensive multi-omic discovery.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Circulating tumor DNA (ctDNA) analysis is a promising tool for cancer genotyping and monitoring.
- Previous studies using targeted approaches have limited our understanding of ctDNA heterogeneity.
- Aggressive prostate cancer presents complex challenges for treatment and monitoring.
Purpose of the Study:
- To comprehensively analyze genomic alterations within ctDNA from patients with aggressive prostate cancer.
- To investigate the evolutionary dynamics of distinct ctDNA populations.
- To identify genomic drivers of acquired resistance to androgen receptor (AR) pathway inhibitors.
Main Methods:
- Deep whole-genome sequencing of serial plasma ctDNA and synchronous metastases.
- Comprehensive assessment of all classes of genomic alterations.
- Analysis of ctDNA before and after treatment with AR pathway inhibitors.
- Inference of mRNA expression and transcription factor activity from ctDNA nucleosome footprints.
Main Results:
- ctDNA harbors multiple dominant populations with distinct evolutionary histories, including whole-genome doubling and shifts in mutational processes.
- Concordance of clonal driver alterations between tissue and ctDNA, with individual metastases contributing minimally to total ctDNA.
- Acquired resistance to AR pathway inhibitors is primarily driven by AR augmentation.
- Nucleosome footprints in ctDNA accurately inferred mRNA expression and AR signaling activity in metastases.
Conclusions:
- ctDNA analysis provides deep insights into cancer evolution and heterogeneity.
- Liquid biopsy enables comprehensive multi-omic discovery, including gene expression and signaling pathway activity.
- Understanding ctDNA dynamics is crucial for monitoring treatment response and identifying resistance mechanisms in prostate cancer.
More Related Videos
12:13Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
07:34Author Spotlight: Advancing Prostate Cancer Research Through Improved Tissue Sampling and Biobanking
Published on: November 17, 2023
