Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

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.M.K.H.H. was supported by scholarships from the National Health and Medical Research Council, Australia, University of Melbourne (Melville Hughes Scholarship) and the Royal Australasian College of Surgeons (Foundation of Surgery Catherine Marie Enright Kelly and ANZ Journal of Surgery Research Scholarships). N.M.C. is the recipient of a David Bickart Clinician Research Fellowship from the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne. M.K. is supported by the Carlo Vaccari Scholarship and APCR.This work is supported by NHMRC project grants 1024081 (N.M.C., J.S.P., A.J.C. and C.M.H.) and 1047581 (C.M.H., G.M., I.H., J.S.P., A.J.C., N.M.C.), as well as a federal grant from the Australian Department of Health and Aging to the Epworth Cancer Centre, Epworth Hospital (A.J.C., N.M.C., C.M.H.). In carrying out this research, we received funding and support from the Victoria Research Laboratory of National ICT Australia (NICTA) and the University of Melbourne, Australia. NICTA is funded by the Australian Government through the Department of Communications and the Australian Research Council through the ICT Centre of Excellence Programme. K.P. is supported by an Addenbrooke’s Charitable Trust Clinical Research Training Fellowship. We thank the Cambridge Urological Biorepository, the Human Research Tissue Bank and Biomedical Research Centre for tissue processing and storage. The Cambridge Urological Biorepostory is supported by the Cambridge Cancer Centre and Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the US Department of Energy. We thank the Cambridge Institute Genomics Core and the Australian Genomics Research Facility for their support with this work. This work was supported by funding from Cancer Research UK C14303/A17197