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

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.