Fig. 7

Chronological progress of prostate carcinogenesis. a, c Analysis of single base substitution (COSMIC SBS) signature 1 mutations (CpG > TpG) shows the evolutionary progression of the cancer in calendar time preceding radical prostatectomy (RP). The median age estimates and 95% confidence intervals (square brackets) of each cluster from simulations starting at random time points up to 15 years before RP are shown. For GP5, the number of tandem duplications (TDs) caused by CDK12 inactivation detected in each evolutionary cluster is shown in the table as their correlation with SBS1 mutations was used to estimate the start of the TD phenotype. b, d Age-referenced cancer subclone cladogram for each patient. The nodes in the trees are shown at the age where a single progenitor cell (most recent common ancestor, MRCA) of the evolutionary cluster emerged and subsequently underwent clonal expansion. The gray line connecting a leaf node to RP shows the longest path (LP) of signature 1 mutations that were used in the timing of the emergence of the evolutionary clusters. Timeline markers for the emergence of the first evolutionary clone and the dominant clone detected in the metastasis are noted as “1st met” and “adv. met”. On the right to the cladogram, plasma total prostate specific antigen (PSA) levels are placed on the timeline in dark gray, together with corresponding percent free PSA values in light gray when available. GP5 received dutasteride and finasteride for symptoms of benign prostatic hyperplasia during the time periods marked with pink and orange boxes