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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.

Original publication

DOI

10.1038/ncomms7605

Type

Journal article

Journal

Nature communications

Publication Date

04/2015

Volume

6

Addresses

1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.

Keywords

Humans, Adenocarcinoma, Bone Neoplasms, Brain Neoplasms, Prostatic Neoplasms, Neoplasm Metastasis, Disease Progression, RNA, Messenger, Longitudinal Studies, Sequence Analysis, DNA, Mutation, Polymorphism, Single Nucleotide, Aged, Middle Aged, Male, Tumor Suppressor Protein p53, DNA Copy Number Variations