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Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer
journal contributionposted on 2020-07-31, 13:09 authored by Matthew KH Hong, Geoff Macintyre, David C Wedge, Peter Van Loo, Keval Patel, Sebastian Lunke, Ludmil B Alexandrov, Clare Sloggett, Marek Cmero, Francesco Marass, Dana Tsui, Stefano Mangiola, Andrew Lonie, Haroon Naeem, Nikhil Sapre, Pramit M Phal, Natalie Kurganovs, Xiaowen Chin, Michael Kerger, Anne Y Warren, David Neal, Vincent Gnanapragasam, Nitzan Rosenfeld, John S Pedersen, Andrew Ryan, Izhak Haviv, Anthony J Costello, Niall M Corcoran, Christopher M Hovens
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.