Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer
Open accessAbstract
BACKGROUND: Prostate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility. OBJECTIVE: To elucidate PC PSMA expression and associate this with defective DNA damage repair (DDR). DESIGN, SETTING, AND PARTICIPANTS: Membranous PSMA (mPSMA) expression was scored immunohistochemically from metastatic castration-resistant PC (mCRPC) and matching, same-patient, diagnostic biopsies, and correlated with next-generation sequencing (NGS) and clinical outcome data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Expression of mPSMA was quantitated by modified H-score. Patient DNA was tested by NGS. Gene expression and activity scores were determined from mCRPC transcriptomes. Statistical correlations utilised Wilcoxon signed rank tests, survival was estimated by Kaplan-Meier test, and sample heterogeneity was quantified by Shannon's diversity index. RESULTS AND LIMITATIONS: Expression of mPSMA at diagnosis was associated with higher Gleason grade (p=0.04) and worse overall survival (p=0.006). Overall, mPSMA expression levels increased at mCRPC (median H-score [interquartile range]: castration-sensitive prostate cancer [CSPC] 17.5 [0.0-60.0] vs mCRPC 55.0 [2.8-117.5]). Surprisingly, 42% (n=16) of CSPC and 27% (n=16) of mCRPC tissues sampled had no detectable mPSMA (H-score <10). Marked intratumour heterogeneity of mPSMA expression, with foci containing no detectable PSMA, was observed in all mPSMA expressing CSPC (100%) and 37 (84%) mCRPC biopsies. Heterogeneous intrapatient mPSMA expression between metastases was also observed, with the lowest expression in liver metastases. Tumours with DDR had higher mPSMA expression (p=0.016; 87.5 [25.0-247.5] vs 20 [0.3-98.8]; difference in medians 60 [5.0-95.0]); validation cohort studies confirmed higher mPSMA expression in patients with deleterious aberrations in BRCA2 (p<0.001; median H-score: 300 [165-300]; difference in medians 195.0 [100.0-270.0]) and ATM (p=0.005; 212.5 [136.3-300]; difference in medians 140.0 [55.0-200]) than in molecularly unselected mCRPC biopsies (55.0 [2.75-117.5]). Validation studies using mCRPC transcriptomes corroborated these findings, also indicating that SOX2 high tumours have low PSMA expression. CONCLUSIONS: Membranous PSMA expression is upregulated in some but not all PCs, with mPSMA expression demonstrating marked inter- and intrapatient heterogeneity. DDR aberrations are associated with higher mPSMA expression and merit further evaluation as predictive biomarkers of response for PSMA-targeted therapies in larger, prospective cohorts. PATIENT SUMMARY: Through analysis of prostate cancer samples, we report that the presence of prostate-specific membrane antigen (PSMA) is extremely variable both within one patient and between different patients. This may limit the usefulness of PSMA scans and PSMA-targeted therapies. We show for the first time that prostate cancers with defective DNA repair produce more PSMA and so may respond better to PSMA-targeting treatments.
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Previous reports have shown that high PSMA expression is associated with poor outcomes in patients with prostate cancer and metastatic castration-resistant prostate cancer.
“These findings contrast with previous reports that high PSMA expression is associated with poor outcomes in patients with prostate cancer and mCRPC (3,4,22).”
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- Authors
- Paschalis, A., Sheehan, B., Riisnaes, R., Rodrigues, D. N., Gurel, B., Bertan, C., Ferreira, A., Lambros, M. B. K., Seed, G., Yuan, W., Dolling, D., Welti, J. C., Neeb, A., Sumanasuriya, S., Rescigno, P., Bianchini, D., Tunariu, N., Carreira, S., Sharp, A., Oyen, W., & de Bono, J. S.
- Affiliations
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- ORCID
- Venue
- European Urology
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 76
- Issue
- 4
- Pages
- 469-478
- ISSN
- 0302-2838 (ISSN-L)
- PMC
- PMC6853166
- OpenAlex
- W2963473092
- Cited by
- 455
- References
- 36
- Citations by year
- 2026: 41 · 2025: 61 · 2024: 78 · 2023: 103 · 2022: 68 · 2021: 62 · 2020: 31 · 2019: 9 · 2017: 1 · 2014: 1
- FWCI
- 31.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Urology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Movember Foundation
- Prostate Cancer UK
- Cancer Research UK
- Prostate Cancer Foundation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Keywords
- prostate-specific membrane antigen, prostate cancer, castration-resistant prostate cancer, DNA repair, intratumoral heterogeneity, BRCA2, BRCA1, TP53, 53BP1, Gleason grade, overall survival, liver metastasis, theranostic biomarkers, gene expression signatures, tumor suppressor, tumor suppressor loss
- MeSH terms
- Antigens, Surface, DNA Repair, Humans, Male, Retrospective Studies, Glutamate Carboxypeptidase II, Prostatic Neoplasms, Castration-Resistant
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