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

Cameron Herberts, Matti Annala, Joonatan Sipola, Sarah W. S. Ng, Xinyi E. Chen, Anssi Nurminen, Olga V. Korhonen, Aslı D. Munzur, Kevin Beja, Elena Schönlau, Cecily Q. Bernales, Elie Ritch, Jack V. W. Bacon, Nathan A. Lack, Matti Nykter, Rahul Aggarwal, Eric J. Small, Martin E. Gleave, David A. Quigley, Felix Y. Feng, Kim N. Chi and Alexander W. Wyatt ()
Additional contact information
Cameron Herberts: University of British Columbia
Matti Annala: University of British Columbia
Joonatan Sipola: Tampere University and Tays Cancer Center
Sarah W. S. Ng: University of British Columbia
Xinyi E. Chen: University of British Columbia
Anssi Nurminen: Tampere University and Tays Cancer Center
Olga V. Korhonen: Tampere University and Tays Cancer Center
Aslı D. Munzur: University of British Columbia
Kevin Beja: University of British Columbia
Elena Schönlau: University of British Columbia
Cecily Q. Bernales: University of British Columbia
Elie Ritch: University of British Columbia
Jack V. W. Bacon: University of British Columbia
Nathan A. Lack: University of British Columbia
Matti Nykter: Tampere University and Tays Cancer Center
Rahul Aggarwal: University of California San Francisco
Eric J. Small: University of California San Francisco
Martin E. Gleave: University of British Columbia
David A. Quigley: University of California San Francisco
Felix Y. Feng: University of California San Francisco
Kim N. Chi: University of British Columbia
Alexander W. Wyatt: University of British Columbia

Nature, 2022, vol. 608, issue 7921, 199-208

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04975-9

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