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Sequencing 424 men at the point their cancer had spread but before hormone treatment failed showed which genetic changes make castration resistance come sooner, and which make it come later.
Clinical-grade targeted tumour sequencing was performed in men with metastatic castration-sensitive prostate cancer at a tertiary referral centre, quantifying copy-number alterations and alterations in predefined oncogenic signalling pathways. Among 424 men, 213 had high-volume disease and 211 low-volume disease, 275 had de novo metastatic disease and 149 metastatic recurrence of earlier non-metastatic disease. Rates of castration resistance and of death were higher in high-volume disease, and high-volume tumours carried more copy-number alterations, with the NOTCH, cell-cycle and epigenetic modifier pathways ranking highest. De novo metastatic disease differed from metastatic recurrence in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (in the inverse direction) and TP53 and to the cell-cycle, WNT (inverse) and MYC pathways, adjusting for disease volume; overall survival differed 2-fold to 4-fold by AR, SPOP (inverse), WNT (inverse) and cell-cycle alterations. PI3K pathway alterations carried no independent prognostic weight.
It fills the gap between the primary-tumour atlases and the castration-resistant series by describing the disease at the moment most treatment decisions are actually made, and it identifies SPOP as a favourable marker rather than a neutral one.
Shares CDK12, Androgen receptor signalling, Driver mutation, Castration-resistant prostate cancer (CRPC).
Shares Androgen receptor signalling, Driver mutation, Castration-resistant prostate cancer (CRPC), p53 / RB / cell-cycle checkpoint.
Shares Clinical Cancer Research, Androgen receptor signalling, Driver mutation, Androgen receptor.
Shares SPOP, Androgen receptor signalling, Wnt / β-catenin, Androgen receptor.
Shares Androgen receptor signalling, Driver mutation, Castration-resistant prostate cancer (CRPC), Androgen receptor.
Shares SPOP, SPOP mutation, Androgen receptor signalling, Driver mutation.
Shares CDK12, Androgen receptor signalling, Castration-resistant prostate cancer (CRPC), Androgen receptor.
Shares Clinical Cancer Research, Castration-resistant prostate cancer (CRPC), p53 / RB / cell-cycle checkpoint, Androgen receptor.