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Sequencing the original diagnostic biopsies of men who later died of prostate cancer showed the dangerous changes were already there at the start, years before the disease became resistant.
Genomic aberrations were studied in primary prostate cancer diagnostic biopsies from men who went on to develop metastatic castration-resistant prostate cancer, with matching same-patient diagnostic and castration-resistant biopsies for a subset. Four hundred and seventy treatment-naive diagnostic biopsies were profiled by targeted and low-pass whole-genome sequencing, with 61 matched castration-resistant biopsies. TP53 was altered in 27% and PTEN in 12%, with DNA damage repair gene defects in BRCA2 at 7%, CDK12 at 5% and ATM at 4%. TP53, BRCA2 and CDK12 mutations were markedly more common than in the TCGA primary cohort. Men whose primary tumour carried RB1 loss had a worse prognosis. Among the 61 men with matched biopsies, differences were identified in AR, TP53, RB1 and PI3K or AKT mutational status between the two time points.
It splits the alterations into two groups with different practical meanings. The repair defects are present at diagnosis at close to their castration-resistant prevalence, so testing early is worthwhile; AR, TP53 and RB1 changes accumulate later, so a diagnostic sample does not answer questions about the disease in front of you at relapse.
Shares Biopsy, ATM, RB1, Androgen receptor signalling.
Shares Biopsy, PTEN, RB1, Androgen receptor signalling.
Shares RB1, Androgen receptor signalling, Driver mutation, Castration-resistant prostate cancer (CRPC).
Shares ATM, Androgen receptor signalling, Double-strand break repair: HR versus end joining, Castration-resistant prostate cancer (CRPC).
Shares CDK12, Androgen receptor signalling, Double-strand break repair: HR versus end joining, Castration-resistant prostate cancer (CRPC).
Shares CDK12, Androgen receptor signalling, Driver mutation, Castration-resistant prostate cancer (CRPC).
Shares Biopsy, PTEN, ATM, Androgen receptor signalling.
Shares PTEN, RB1, Castration-resistant prostate cancer (CRPC), p53 / RB / cell-cycle checkpoint.