Prostate Cancer in your Genes
Interactive Figure
Bottom Line Up Front (BLUF)
A new genetic score called PRSagg, developed from DNA data on nearly 40,000 veterans, can predict how aggressive a man's prostate cancer is likely to be — independent of PSA, age, or biopsy grade. In the largest validation study of its kind, men with the highest PRSagg had more than twice the risk of their cancer spreading (metastasis) compared to men with the lowest score. Crucially, this score is calculated once from a blood or saliva sample and never changes. Combined with a related score called PRSPSA, it can sort men on active surveillance into meaningful low-, middle-, and high-risk groups. Although not yet a clinical standard of care, the science behind this approach is advancing rapidly, with a related VA national trial already enrolling veterans. This is a story worth paying close attention to.
The Challenge Active Surveillance Patients Know Too Well
If you are on active surveillance (AS) for low-grade prostate cancer, you are living with an uncomfortable uncertainty: Will this cancer stay quiet for the rest of my life, or will it eventually declare itself dangerous? Right now, your doctor watches for warning signs through repeated PSA tests, MRI scans, and periodic biopsies. But none of these tools tell you definitively whether your underlying biology is prone to aggressive behavior.
That missing piece may be closer to reality. A team of researchers from UC San Diego, the VA San Diego Healthcare System, the VA Boston Healthcare System, and a large international consortium has published a major new study describing a genetic score — derived entirely from common DNA variants present in your body since birth — that predicts the odds of developing aggressive prostate cancer. The score is called PRSagg, shorthand for Polygenic Risk Score for Aggressiveness.
This is not the first genetic score for prostate cancer. But it is the first specifically designed to answer a different question: not just "Do I have an elevated risk of getting prostate cancer?" but "If I have prostate cancer, how biologically aggressive is it likely to be?"
A Plain-English Genetics Primer: What Is a Polygenic Score?
Your DNA carries about three billion "letters." Scattered throughout that sequence are hundreds of places where one letter differs from person to person — called single nucleotide polymorphisms, or SNPs (pronounced "snips"). Most SNPs have no meaningful effect on their own. But when researchers study hundreds of thousands of men with and without prostate cancer and track which SNP combinations tend to appear in men whose cancer behaves aggressively, they can assemble a weighted scorecard.
That scorecard is a polygenic risk score: a single number summarizing the cumulative small effects of many genetic variants. Think of it like a credit score — no single late payment makes or breaks your credit, but the overall pattern of financial behavior produces a predictive number. In the same way, PRSagg adds up 172 genetic variants across your genome to produce a score that correlates with cancer grade and behavior.
The power of this approach is that your DNA never changes. You only need to be genotyped once in your lifetime. The score does not require a biopsy, does not fluctuate with infection the way PSA does, and does not depend on your age or ancestry (those factors are accounted for separately in the analysis).
About This Study: Scale, Rigor, and Validation
This new research, posted to the preprint server medRxiv on May 10, 2026, was led by George Xu, Roshan Karunamuni, and Dr. Tyler Seibert at UC San Diego, with collaborators at the VA Boston Healthcare System, the University of Pennsylvania, and a sweeping international consortium called PRACTICAL, which includes research centers across the United States, United Kingdom, Europe, Australia, and beyond.
The study used three separate, large datasets:
Training dataset — the Million Veteran Program (MVP). The MVP is the largest genomic biobank in the United States, maintained by the U.S. Department of Veterans Affairs. This study drew on 38,688 male veterans diagnosed with prostate cancer, each of whom had a confirmed Gleason score on biopsy. The researchers conducted a genome-wide search across all these men to find which genetic variants correlated with higher biopsy grade group — the standard measure of cancer aggressiveness (grades 1 through 5, with grade 1 being the least aggressive and grade 5 the most). Using a mathematical technique called LASSO regularization, they identified 172 SNPs that, taken together, formed the PRSagg score.
External validation dataset — the PRACTICAL Consortium. The finding was then independently tested in a completely separate database of 44,802 men from the PRACTICAL Consortium — a diverse, international research partnership. Finding the same result in a population that had no role in building the score is considered the gold standard of scientific validation.
Active monitoring validation — the ProtecT Trial. Perhaps the most clinically compelling dataset was a subset of 316 participants from the landmark ProtecT randomized controlled trial in the United Kingdom, all of whom were placed on active monitoring (the British equivalent of active surveillance) and followed over time for actual outcomes — including whether they developed metastatic disease.
Key Findings at a Glance
- In the MVP training set, each one-standard-deviation increase in PRSagg raised the odds of being in a higher biopsy grade group by 53% (OR = 1.53).
- In the PRACTICAL validation (44,802 men), the same relationship held, with a 9% increased odds per standard deviation (OR = 1.09) — a smaller effect size expected in external populations, but still statistically robust.
- In the ProtecT active monitoring cohort, each standard deviation increase in PRSagg was associated with a 2.15-fold increased risk of metastasis (OR = 2.15; 95% CI: 1.02–3.88).
- The companion score PRSPSA (which measures genetic predisposition to benign PSA elevations) was also protective: each standard deviation increase cut the risk of metastasis by 44%.
- Among men with a high genetic risk of developing any prostate cancer (high PHS601 score), combining PRSagg and PRSPSA into a single "Aggressivity Risk Group" (ARG) produced a nearly 8-fold range in estimated lifetime risk of metastatic disease — from 1.0% to 7.7% by age 85 among European-ancestry men.
- PRSagg also stratified risk of eventual metastasis for men of African ancestry who are at already-elevated baseline risk — a particularly important finding for health equity.
Why This Matters Most for Men on Active Surveillance
The clinical home for PRSagg is active surveillance. The whole premise of AS is that most low-grade prostate cancers never become life-threatening — so why expose men to the side effects of surgery or radiation unnecessarily? But the process has a flaw: some men on AS have cancers that will eventually upgrade to dangerous grades, spread, and require urgent treatment. The challenge is identifying those men before things go wrong, ideally at the time of initial diagnosis.
This is exactly what PRSagg attempts to address. The researchers specifically tested whether PRSagg predicted "unfavorable outcomes" in a large group of MVP veterans who were managed conservatively — similar to AS patients — and found that each standard deviation increase in PRSagg raised the odds of an unfavorable outcome (Gleason upgrade to grade 4–5, metastasis, or biochemical recurrence after treatment) by 13%. While modest on its own, this effect is independent of PSA, age, ancestry, and other known risk factors.
Critically, the ProtecT active monitoring validation showed a much stronger 2.15-fold metastasis risk signal. This suggests that in truly carefully watched, early-stage patients, PRSagg has meaningful power to separate those whose cancer will behave from those whose cancer will eventually declare itself dangerous.
The table below, reconstructed from Figure 1 of the paper, shows how the combination of PRSagg and PRSPSA stratifies the risk of developing grade group 3 or higher disease at diagnosis in the MVP training dataset:
| PRSagg Category | PRSPSA High (lots of benign PSA risk) |
PRSPSA Mid | PRSPSA Low (PSA driven by cancer) |
|---|---|---|---|
| PRSagg Low | 18.2% | 21.5% | 25.2% |
| PRSagg Mid | 28.6% | 31.6% | 36.2% |
| PRSagg High | 42.7% | 46.3% | 53.0% |
Table: Cumulative incidence (%) of grade group ≥3 at diagnosis in the MVP dataset, by combinations of PRSagg and PRSPSA risk category. The "best-case" genetic profile (low PRSagg, high PRSPSA) yields 18.2% risk; the "worst-case" (high PRSagg, low PRSPSA) yields 53.0%.
The Bigger Picture: This Is Part of a Fast-Moving Field
PRSagg does not stand alone. It is the latest advance in a rapidly converging set of scientific developments around genomics and prostate cancer. Here is the recent landscape:
The BARCODE1 Trial (New England Journal of Medicine, April 2025). This landmark UK screening study — the first of its kind — used a polygenic risk score built from 130 prostate cancer variants to identify men in the top 10% of genetic risk for prostate cancer in the general population. Of 6,393 men whose PRS was calculated, 745 were in the top risk tier and invited for MRI-guided biopsy regardless of PSA level. The result: 40% were found to have prostate cancer, and 55% of those cancers were intermediate or high risk requiring treatment. Most strikingly, 71% of treatment-warranting cancers would have been completely missed by the standard UK diagnostic pathway based on PSA alone. BARCODE1 demonstrated that PRS-based screening can find more clinically important cancers and fewer indolent ones — precisely what PSA screening has struggled to achieve.
Canary PASS / JAMA Oncology (February 2025). The Canary Prostate Active Surveillance Study — a prospective multicenter U.S. study that has followed 1,220 AS patients for a median of 5.3 years — found that established polygenic scores (PRS-451 and PRS-400) are significantly associated with the risk of Gleason grade upgrading during surveillance. Men in the top quintile of PRS-400 had twice the risk of any upgrading and twice the risk of extreme upgrading (from grade group 1 or 2 all the way to grade group 3 or higher) compared to men in the lowest quintile. This study directly reinforced the clinical relevance of genetic scores in the active surveillance setting — the same clinical setting PRSagg is designed for.
The ProGRESS Trial / Nature Cancer (January 2026). The VA-led ProGRESS study (Prostate Cancer, Genetic Risk, and Equitable Screening Study; NCT05926102) represents the operational bridge between research and practice. Researchers at VA Boston, UC San Diego, and the Broad Institute developed the P-CARE model — combining PHS601, family history, and genetic ancestry across 585,000 male MVP participants — and validated it across diverse ethnic populations. This model is now powering a national randomized controlled trial that began enrolling veterans in November 2024. Participants aged 55–69 who have never had prostate cancer provide a saliva sample; the genetic risk report guides whether and when they should be screened. If this trial succeeds, it could set the template for routine genetic risk stratification in primary care. ProGRESS and PRSagg share the same research lineage — the same VA data infrastructure, many of the same investigators, and the same scientific philosophy.
Timeline: Polygenic Scores Advancing Toward the Clinic
What Genes Are Involved? The Biology Behind the Score
The 172 variants in PRSagg are not random. Several map to genes already known to be important in prostate cancer biology:
KLK3/KLK2 cluster. Multiple PRSagg variants sit near the genes encoding the kallikrein proteins — including KLK3, the gene that produces prostate-specific antigen (PSA) itself. This helps explain why separating "PSA genetics" from "aggressiveness genetics" is so important: some men have genetically elevated PSA that has nothing to do with cancer risk, while others have PSA driven by actual tumor biology.
TERT. One variant maps to the telomerase reverse transcriptase gene — one of the most well-established cancer susceptibility loci across many cancer types. Telomere maintenance is closely tied to how cells age and mutate.
IRX4. A known prostate cancer risk gene that regulates androgen signaling — the hormonal pathway that drives most prostate cancer growth.
LMTK2. Directly implicated in androgen receptor signaling and previously identified in prostate cancer genome-wide association studies.
PCAT1. A prostate cancer-specific oncogenic long non-coding RNA — one of a class of genetic molecules that regulate gene expression and have been associated with cancer progression.
This biological coherence — the fact that PRSagg variants cluster around known cancer-driving pathways — increases confidence that the score is capturing genuine biology rather than statistical coincidence.
A Note on Health Equity: Black Men and This Research
African American men are disproportionately burdened by prostate cancer: they are roughly 70% more likely to develop it and more than twice as likely to die from it compared to white men. The causes are complex, involving inherited biological factors, differences in healthcare access, and social determinants of health.
The PRSagg study specifically included men of African ancestry — 30.6% of the MVP training set — and demonstrated that the genetic aggressivity risk grouping (PRSagg/psa group) stratified metastatic prostate cancer risk in both European-ancestry and African-ancestry men who had high overall genetic risk (high PHS601). This is significant. Many earlier genetic tools were developed almost entirely in European-ancestry populations and performed poorly in others. The fact that this score provides stratification across ancestries — even if further refinement is needed — represents meaningful progress.
The researchers were also candid that the higher odds ratios seen for non-European ancestry men in their models (including East Asian men) likely reflect a combination of inherited biology and systemic health inequities, and that larger ancestry-specific datasets are needed to fully disentangle these contributions.
Caveats and Limitations: What the Study Cannot Yet Tell Us
The researchers are thorough and honest about what this study does not yet establish:
It is a preprint, not yet peer-reviewed. The findings have not yet been formally scrutinized by independent experts through the journal peer-review process. The results are promising but should be understood as preliminary until that process is complete.
Association is not causation. PRSagg predicts aggressiveness; it does not explain all of the biology behind it. The score captures common inherited variants but not rare high-penetrance mutations (like BRCA2), structural DNA changes, or epigenetic regulation — any of which can also drive aggressiveness.
The active monitoring cohort in MVP is approximate. Because formal AS status is not recorded in the VA's electronic records, the researchers identified a conservative management cohort by inference — men who went more than a year after diagnosis without treatment. This approximation may introduce noise.
The ProtecT metastasis signal involves small numbers. Only 27 men in the 316-person ProtecT subset developed metastasis — a small absolute number, even though the statistical result is significant. Larger prospective datasets are needed to confirm this finding.
No clinical utility has yet been proven. A score that predicts outcomes is necessary but not sufficient for clinical implementation. What is needed next: prospective studies showing that acting on PRSagg results — say, intensifying surveillance for high-risk men or safely de-escalating it for low-risk men — actually improves patient outcomes without causing harm. That evidence is not yet in hand.
Important Caution for Patients
PRSagg is not currently available as a clinical test, and it is not part of any current standard-of-care guideline for prostate cancer (NCCN, AUA, or EAU). A 2026 Nature Reviews Urology commentary specifically noted that while polygenic scores for prostate cancer have strong analytical and clinical validity evidence, "evidence firmly establishing clinical utility beyond modelling studies is still lacking." Do not make any changes to your active surveillance protocol, biopsy schedule, or treatment plan based on this research alone. Bring this study to your oncologist or urologist and ask how the emerging field of polygenic scoring might apply to your individual situation.
How Quickly Could This Become Standard of Care?
For patients understandably eager for a concrete answer: the honest response is "probably not before the end of this decade for most clinical settings, but the trajectory is encouraging." Here is the pathway that science must travel:
Step 1: Peer review and publication. This preprint needs to complete the peer-review process and be published in a major journal — probably within 6–18 months if the findings hold up.
Step 2: Prospective validation and clinical utility trials. The ProGRESS trial (now recruiting) is doing exactly this for the screening version of the score. A parallel effort — testing whether PRSagg information actually improves active surveillance decision-making — would likely need to be demonstrated in a randomized or registry-based trial.
Step 3: Regulatory and laboratory infrastructure. The test itself would need to be validated as a clinical assay — either through FDA clearance or as a Laboratory Developed Test — and implemented through CLIA-certified clinical labs. The Broad Clinical Labs / VA partnership powering ProGRESS shows this pipeline already exists and is functional.
Step 4: Guideline adoption. Major bodies like NCCN, AUA, and EAU would need to review the accumulated evidence and issue formal guidance. This process typically takes 2–5 years after strong prospective data emerge.
There is genuine reason for optimism about the pace. The VA's Million Veteran Program gives this line of research an unmatched dataset and an operational implementation pathway. The Broad Clinical Labs "blended genome-exome" assay powering ProGRESS is already a low-cost, scalable, clinical-grade genetic test. And the regulatory pathway for germline genetic tests — as distinct from tumor biomarkers or drugs — is well-established. If the ProGRESS trial succeeds and PRSagg validation holds up in prospective AS cohorts, an optimistic (but not implausible) scenario sees PRSagg informing AS management in academic medical centers by the early 2030s, with broader diffusion following.
Questions to Ask Your Doctor
If you are on active surveillance or have early-stage prostate cancer and want to be an informed participant in where this science is heading, consider raising these questions at your next appointment:
"Have you seen the new VA study on PRSagg — the polygenic score for prostate cancer aggressiveness? Is this something we should be watching?" · "Am I potentially eligible for the ProGRESS trial or similar genomic research studies?" · "Have I had germline genetic testing, and if so, do my results tell us anything about BRCA2, ATM, or other high-penetrance variants relevant to my prostate cancer?" · "As polygenic scores become available clinically, what would need to be true about my risk profile for you to consider intensifying or de-escalating my active surveillance protocol?"
Glossary of Key Terms
- Active Surveillance (AS)
- A management strategy for low- and select intermediate-risk prostate cancer involving regular monitoring (PSA, MRI, biopsies) rather than immediate treatment, with the option to treat if the cancer progresses.
- Genome-Wide Association Study (GWAS)
- A research approach that scans the entire genome of large populations to find genetic variants (SNPs) associated with a particular disease or trait.
- Gleason Score / Grade Group
- The primary pathological measure of prostate cancer aggressiveness, based on biopsy. Grade groups run from 1 (least aggressive) to 5 (most aggressive). Grade group 3 or higher generally triggers treatment consideration.
- LASSO Regularization
- A statistical technique that selects the most important variables from a large candidate list while reducing overfitting — in this context, identifying which of many hundreds of SNPs actually contribute meaningfully to the aggressiveness score.
- Million Veteran Program (MVP)
- The world's largest genomic biobank, maintained by the U.S. Department of Veterans Affairs, with DNA and health records from over one million U.S. veterans. It is the foundation dataset for PRSagg and the ProGRESS trial.
- Odds Ratio (OR)
- A measure of association. An OR of 1.53 means men with one standard deviation higher PRSagg have 53% higher odds of a worse outcome. An OR of 2.15 means 2.15 times the odds — roughly doubled risk.
- P-CARE Model
- Prostate CAncer integrated Risk Evaluation — the VA/Broad Institute clinical risk model combining PHS601 (601-variant polygenic hazard score), family history, and genetic ancestry, now being tested in the ProGRESS randomized trial.
- Polygenic Risk Score (PRS)
- A weighted sum of the effects of many common genetic variants (SNPs) that together estimate an individual's inherited predisposition to a disease or trait.
- PRSagg
- The new 172-variant polygenic risk score for prostate cancer aggressiveness, the subject of this article. Predicts likelihood of aggressive disease independent of PSA, age, and ancestry.
- PRSPSA
- A polygenic score for genetically elevated PSA that is not driven by cancer. High PRSPSA is associated with lower risk of aggressive cancer because it explains the PSA elevation as benign rather than tumor-driven.
- Single Nucleotide Polymorphism (SNP)
- A position in the genome where a single DNA "letter" varies among individuals. Common SNPs individually have tiny effects on disease risk, but many together, weighted appropriately, can produce meaningful predictive scores.
- Standard Deviation (SD)
- A statistical unit measuring how far a score is from the average. In this study, "per standard deviation increase" means for every step up in genetic risk equal to one SD above the mean.
Verified Sources and Formal Citations
-
Primary Study (this article's focus) — PRSagg preprint:
Xu G, Karunamuni R, Dornisch AM, et al. Germline polygenic score for prostate cancer aggressiveness. medRxiv. Posted May 10, 2026. doi:10.64898/2026.05.07.26352488
https://doi.org/10.64898/2026.05.07.26352488
NOTE: This is a preprint that has not yet been certified by peer review. -
BARCODE1 — PRS Screening Trial in NEJM:
McHugh JK, Bancroft EK, Saunders E, et al; BARCODE1 Steering Committee and Collaborators. Assessment of a polygenic risk score in screening for prostate cancer. N Engl J Med. 2025;392(14):1406–1417. doi:10.1056/NEJMoa2407934
https://www.nejm.org/doi/abs/10.1056/NEJMoa2407934 -
Canary PASS / PRS and Active Surveillance Upgrading (JAMA Oncology):
Goss LB, Liu M, Zheng Y, et al. Polygenic risk score and upgrading in patients with prostate cancer receiving active surveillance. JAMA Oncol. 2025;11(2):168–171. doi:10.1001/jamaoncol.2024.5398
https://pmc.ncbi.nlm.nih.gov/articles/PMC11843374/ -
ProGRESS / P-CARE Model (Nature Cancer):
Vassy JL, Dornisch AM, Karunamuni R, et al. Genomic risk model to implement precision prostate cancer screening in clinical care: the ProGRESS study. Nat Cancer. 2026;7(2):352–367. doi:10.1038/s43018-025-01103-0
https://www.nature.com/articles/s43018-025-01103-0 -
ProGRESS Clinical Trial Registration:
The Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS). ClinicalTrials.gov identifier NCT05926102.
https://clinicaltrials.gov/study/NCT05926102 -
VA Description of ProGRESS for Veterans:
U.S. Department of Veterans Affairs Office of Research and Development. Testing the ProGRESS of precision prostate cancer screening. Published January 8, 2025.
https://www.research.va.gov/currents/0125-Testing-the-ProGRESS-of-precision-prostate-cancer-screening.cfm -
Broad Institute / VA Blended Genome-Exome Test for ProGRESS:
Broad Institute News. Clinical trial explores whether a genetic test can improve early detection of prostate cancer. Published February 9, 2026.
https://www.broadinstitute.org/news/clinical-trial-explores-whether-genetic-test-can-improve-early-detection-prostate-cancer -
Clinical Translation of PRS / Nature Reviews Urology (2026 commentary on readiness):
Clinical translation of polygenic scores for prostate cancer screening. Nat Rev Urol. 2026;23:256–265.
https://www.nature.com/articles/s41585-025-01095-7 -
ProtecT Trial 15-Year Outcomes (key background reference):
Hamdy FC, Donovan JL, Lane JA, et al. Fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med. 2023;388(17):1547–1558. doi:10.1056/NEJMoa2214122
https://www.nejm.org/doi/full/10.1056/NEJMoa2214122 -
PHS601 / Polygenic Risk of Metastatic Prostate Cancer in MVP:
Pagadala MS, Lynch J, Karunamuni R, et al. Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program. J Natl Cancer Inst. 2023;115(2):190–199. doi:10.1093/jnci/djac199
https://pubmed.ncbi.nlm.nih.gov/36315017/ -
BARCODE1 Coverage (OncLive):
Prostate Cancer Testing Via Polygenic Risk Score Outperforms Standard Approaches. OncLive. April 2026.
https://www.onclive.com/view/prostate-cancer-testing-via-polygenic-risk-score-outperforms-standard-approaches -
Polygenic Risk Scores in Prostate Cancer — 2026 Clinical Review:
Polygenic Risk Scores in Prostate Cancer. esanum. January 14, 2026.
https://www.esanum.com/today/posts/polygenic-risk-scores-in-prostate-cancer -
Active Surveillance PRS Coverage / Clinical Commentary:
Polygenic Risk Score May Be Useful in Prostate Cancer Active Surveillance. Renal and Urology News. January 8, 2025.
https://www.renalandurologynews.com/features/polygenic-risk-score-may-be-useful-in-prostate-cancer-active-surveillance/
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