The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localised prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features.

Early tumour development is characterised by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumours rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumours frequently do (61%).

The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localised prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumours suitable for active surveillance.