Polygenic Risk Scores in Prostate Cancer

New data from 2024–2025 show how polygenic risk scores may refine prostate cancer screening and risk stratification, improving early detection while raising important clinical and ethical challenges.

A changing landscape in prostate cancer risk assessment

Prostate cancer is the most frequently diagnosed malignancy in men, and early detection remains a central challenge. While PSA testing has improved diagnosis, it also contributes to overdiagnosis of indolent tumours and exposes many patients to unnecessary procedures. This tension between benefit and harm is driving the search for more precise tools capable of identifying men who are genuinely at higher risk of clinically significant disease.

Among the most promising of these tools are polygenic risk scores (PRS), which combine the small contributions of hundreds of common genetic variants to estimate an individual’s inherited susceptibility to prostate cancer. Over the past two years, new evidence has expanded our understanding of how PRS might integrate into screening strategies, refine active surveillance, and support more personalised clinical pathways.

Understanding the genetic basis: what PRS actually measure

PRS quantify lifetime genetic predisposition, aggregating the effect of numerous low-penetrance variants identified through genome-wide association studies. For prostate cancer, current PRS incorporate well over a hundred validated variants, capturing a substantial portion of inherited risk.

These scores can differentiate men with markedly different baseline risks: individuals in the highest PRS percentiles may have a two- to three-fold higher lifetime probability of developing prostate cancer compared with the general population. Importantly, PRS reflect inherited baseline susceptibility, not tumour behaviour. Their strength lies in identifying who is most likely to develop prostate cancer (not necessarily who will develop aggressive disease).

Another critical consideration is ancestry: most PRS have been developed in men of European background, and their performance in other populations is less reliable. This raises equity concerns and highlights the need for ancestry-adjusted or population-specific PRS models.

PRS and early detection

Recent prospective data indicate that PRS can meaningfully refine early-detection strategies when used alongside established tools such as PSA and MRI. Men with very high genetic risk appear more likely to harbour prostate cancer, even when PSA levels are not markedly elevated. Incorporating PRS into screening algorithms could therefore help select younger men or those with borderline PSA values who might benefit from earlier MRI or biopsy.

Equally important, PRS might reduce overinvestigation among low-risk individuals, avoiding unnecessary imaging or biopsies in men whose lifetime genetic risk is minimal. This dual potential - enhancing detection of clinically meaningful disease while reducing harm in low-risk groups - is one of the most compelling arguments for integrating PRS into risk-adapted screening frameworks.

However, evidence also suggests that while PRS improve identification of cancer, their ability to preferentially detect clinically significant tumours is only partial. They enrich for aggressive disease but do not yet eliminate overdiagnosis, underscoring the need to combine PRS with PSA kinetics, MRI findings and clinical judgement.

PRS within active surveillance: refining risk stratification

In addition to informing early detection, PRS may have value in the management of men already diagnosed with low-risk prostate cancer. Data from active surveillance cohorts suggest that higher PRS values are associated with a greater probability of histological upgrading during follow-up, an event that typically triggers reconsideration of definitive treatment.

These observations raise the possibility that PRS could help stratify follow-up intensity:

PRS alone should not determine clinical decisions in active surveillance, but they may become part of a multi-parameter assessment that includes MRI characteristics, PSA density and tumour volume. Their role is complementary, adding a layer of inherited risk biology to the existing framework.

What PRS can/cannot offer right now

The emerging evidence demonstrates several clear strengths of PRS:

  1. they provide stable, lifelong estimates of inherited risk that do not fluctuate over time.
  2. they help identify men who might benefit from earlier or more intensive screening.
  3. they may assist in personalising surveillance pathways, adding genetic context to clinical and imaging data.

But there are equally important limitations:

  1. PRS do not reliably distinguish aggressive from indolent cancer, and therefore cannot independently guide biopsy decisions;
  2. they currently perform unevenly across ancestries, raising concerns about equity in implementation;
  3. their long-term impact on cancer-specific mortality, overdiagnosis and overtreatment remains unknown;
  4. integrating PRS into clinical workflows requires careful communication to avoid misinterpretation or undue anxiety.

In practice, PRS should be considered adjunctive tools, useful for refining risk, not replacing established screening methods or clinical criteria.

How should clinicians use PRS in 2025?

For clinicians, the key question is not whether PRS work, but how they can be incorporated sensibly into patient management. Current evidence supports their use in:

Nevertheless, decisions should always combine PRS with PSA behaviour, MRI findings, pathology, and patient preferences. PRS add context, not conclusions.

Sources
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