10779/crick.12746171.v1 Matthew KH Hong Matthew KH Hong Geoff Macintyre Geoff Macintyre David C Wedge David C Wedge Peter Van Loo Peter Van Loo Keval Patel Keval Patel Sebastian Lunke Sebastian Lunke Ludmil B Alexandrov Ludmil B Alexandrov Clare Sloggett Clare Sloggett Marek Cmero Marek Cmero Francesco Marass Francesco Marass Dana Tsui Dana Tsui Stefano Mangiola Stefano Mangiola Andrew Lonie Andrew Lonie Haroon Naeem Haroon Naeem Nikhil Sapre Nikhil Sapre Pramit M Phal Pramit M Phal Natalie Kurganovs Natalie Kurganovs Xiaowen Chin Xiaowen Chin Michael Kerger Michael Kerger Anne Y Warren Anne Y Warren David Neal David Neal Vincent Gnanapragasam Vincent Gnanapragasam Nitzan Rosenfeld Nitzan Rosenfeld John S Pedersen John S Pedersen Andrew Ryan Andrew Ryan Izhak Haviv Izhak Haviv Anthony J Costello Anthony J Costello Niall M Corcoran Niall M Corcoran Christopher M Hovens Christopher M Hovens Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer The Francis Crick Institute 2020 Adenocarcinoma Aged Bone Neoplasms Brain Neoplasms DNA Copy Number Variations Disease Progression Humans Longitudinal Studies Male Middle Aged Mutation Neoplasm Metastasis Polymorphism, Single Nucleotide Prostatic Neoplasms RNA, Messenger Sequence Analysis, DNA Tumor Suppressor Protein p53 Van Loo 2020-07-31 13:09:40 Journal contribution https://crick.figshare.com/articles/journal_contribution/Tracking_the_origins_and_drivers_of_subclonal_metastatic_expansion_in_prostate_cancer/12746171 Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.