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.
Nature. 2022 Jul 20 [Epub]
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, SU2C/PCF West Coast Prostate Cancer Dream Team , David A Quigley, Felix Y Feng, Kim N Chi, Alexander W Wyatt
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada., Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere, Finland., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. .