The molecular heterogeneity and clinical impact of genomic driver alterations in prostate cancer.

Prostate cancer is a common malignancy with a heterogeneous disease course. Prior studies have identified a paucity of point mutations in protein-coding genes and only a few clinically relevant driver alterations. Here, using the Pan Prostate Cancer Group whole genome sequencing dataset from 1001 men, we perform an integrative analysis of cancer driver genes by quantifying recurrent genomic alterations among small mutations, structural variants, and copy number alterations in 961 primary prostate tumour samples. We identify at least one recurrent somatic or germline alteration in 97% of tumours and identify putative driver genes and mechanisms of dysregulation including frequently altered regulatory elements. A prominent example is the activation of oncogenes by structural variation-mediated hijacking of onco-enhancers of the solute carrier gene family including SLC30A4. Other recurrent alterations including FOXA1, MDM4, COL5A1, TP53, and BRCA1 stratify with metastatic disease, with additional drivers enriched in African-ancestry tumours. One quarter of tumours have acquired genome-informed therapeutic targets. Unsupervised analysis of alterations reveals four oncotypes with distinct genetic and clinical characteristics, including two clinically unfavourable oncotypes with shorter metastasis-free survival. Our study uncovers the full spectrum and recurrence patterns of genomic driver alterations in primary prostate cancers and delivers targets for biomarker development, mechanistic studies, and potential therapeutic interventions.