# Genomics of lethal prostate cancer at diagnosis and castration resistance

Source: https://onco.cc/key-papers/paper-mateo-genomics-lethal-prostate-diagnosis-castration-resistance-jci-2020/  
OnCo record `paper-mateo-genomics-lethal-prostate-diagnosis-castration-resistance-jci-2020` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Journal of Clinical Investigation
- Year: 2020
- DOI: 10.1172/JCI132031
- Authors: Mateo J, Seed G, Bertan C, et al.
- Findings: TP53 altered in 27% and PTEN in 12% of diagnostic biopsies from men who later developed castration-resistant disease.; BRCA2 7%, CDK12 5% and ATM 4% at diagnosis, similar to the prevalence in castration-resistant disease.; RB1 loss in the primary tumour associated with worse prognosis.; AR, TP53, RB1 and PI3K/AKT status differed between paired diagnostic and castration-resistant samples.
- What it means: 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.
- Caveats: Selected by outcome: these are the primaries of men who went on to die of the disease, so the prevalences are not those of prostate cancer generally.; Targeted and low-pass sequencing on archival diagnostic biopsies, which are small and often decades old.; Sixty-one matched pairs is a small number on which to describe evolution.

## Sources

- Mateo et al., J Clin Invest 2020: genomics of 470 diagnostic biopsies from men who went on to develop metastatic castration-resistant disease, with 61 matched later biopsies: https://doi.org/10.1172/JCI132031
- PubMed: https://pubmed.ncbi.nlm.nih.gov/31874108/

## Connected records

- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [ATM](https://onco.cc/targets/atm/), [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [CDK12](https://onco.cc/targets/cdk12/), [PTEN](https://onco.cc/targets/pten/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Androgen receptor signalling](https://onco.cc/pathways/ar-signaling/), [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/)
- terms: [Biopsy](https://onco.cc/terms/biopsy/), [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Driver mutation](https://onco.cc/terms/driver-mutation/)
- journals: [Journal of Clinical Investigation](https://onco.cc/journals/jci/)

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