One is in his seventies, has limited access to healthcare, and has accumulated decades of environmental exposures such as smoking and less healthy lifestyle. The other is in his forties, sees his doctor regularly, and has had fewer such exposures over his lifetime. Would their DNA predict their cancer risk equally well? According to a new study, published in the American Journal of Human Genetics, the answer is no, and that distinction could reshape how we use genetics in cancer screening.
Unlike single-gene tests which flag rare mutations, a polygenic risk score (PRS) aggregates the small individual effects of hundreds or thousands of common genetic variants scattered across the genome. No single variant tells you much on its own; but combined, they paint a picture of a person's inherited predisposition to a disease. The PRS tested in this study incorporates 451 prostate cancer risk variants identified through the largest and most diverse prostate cancer genome-wide association study conducted to date. Researchers then validated it using data from the All of Us Research Program, a National Institutes of Health initiative that has enrolled a deliberately diverse participant population with 7,577 prostate cancer cases and over 90,000 controls spanning six genetic ancestry groups.
The PRS showed strong associations with prostate cancer risk across all six ancestry groups studied, including European, African, American, East Asian, South Asian, and Middle Eastern. Put simply, a higher genetic risk score translated to a meaningfully greater chance of prostate cancer; an effect seen across all groups, ranging from a 61% increased risk in men of Middle Eastern ancestry to a 119% increased risk in those of American ancestry. Crucially, men in the top 10% of PRS had roughly four times the prostate cancer risk compared to those with average scores across multiple ancestry groups.
"One of the most significant contributions of our work is demonstrating that a multi-ancestry prostate cancer PRS performs robustly across diverse populations, including groups that have been historically underrepresented in genetic studies," said lead author Shuyan Cheng. "We observed notably strong risk stratification: individuals in the top PRS decile had around 4-fold higher risk compared to those with average scores, which is notably higher than what is typically seen for many other complex traits."
To put that in perspective: while roughly 10% of the population falls into a high-PRS category, only about 0.2% carry rare BRCA2 variants; meaning a well-validated PRS has the potential to flag a far larger share of high-risk individuals who might benefit from earlier or more intensive screening.
The PRS was most predictive in younger men, with the strength of the association declining with age. This is consistent with the broader principle that genetic factors tend to drive risk more strongly earlier in life, before environmental exposures accumulate. Smoking status also mattered. The PRS was most strongly associated with prostate cancer risk in never-smokers and former smokers, and somewhat less so in current smokers. This also fits a pattern seen across other traits that genetic risk scores tend to perform better when environmental risk factors are lower.
However, the relationship with BMI did not follow this trend. Men with higher BMI actually showed stronger PRS associations than those with normal weight, the opposite of what the environmental-exposure logic would predict. "This raises new questions about the role of detection and screening bias,” Cheng said. Higher BMI is associated with lower circulating PSA levels and can make physical exams less sensitive, meaning prostate cancer is more likely to go undetected until it's more advanced, which Cheng suggests, is precisely why the PRS could help: “It could potentially help improve risk stratification in populations where traditional screening is less effective." Healthcare access also emerged as a relevant factor, with men who had recently seen a general physician showing stronger PRS-cancer associations, likely reflecting that those with regular medical contact are more likely to receive a diagnosis.
As part of the same study, the team also conducted a phenome-wide association study (PheWAS), testing whether the prostate cancer PRS was associated with thousands of other clinical outcomes in the All of Us data. The results were reassuring: the PRS was significantly associated with 14 outcomes, nearly all directly tied to prostate cancer itself, including elevated PSA, conditions that commonly result from treatment (urinary incontinence, erectile dysfunction, radiation effects), and signs of disease progression (bone metastasis, the most common site where prostate cancer spreads). Notably, the PRS was not associated with unrelated cancers, such as breast cancer, suggesting the score is capturing prostate-specific biology rather than general cancer susceptibility.
"Moving forward, an important direction for our research is to better understand how PRS can be integrated with clinical and behavioral factors to optimize screening strategies," Cheng said. "Future work will focus on translating these findings into clinical settings and evaluating the clinical utility of PRS."
This research was supported by the National Cancer Institute, the Prostate Cancer Foundation, the Fred Hutch Translational Data Science Initiative, the Andy Hill Cancer Research Endowment, and the Institute for Prostate Cancer Research.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Burcu Darst contributed to this research.
Cheng, S., Suger, A. H., Goss, L. B., Zhang, J., Fuller, H., Guo, B., Lindström, S., & Darst, B. F. (2026). Validation and context-dependent effects of a prostate cancer polygenic risk score in the All of Us Research Program. American journal of human genetics, 113(2), 392–398.
Science Spotlight writer Darya Moosavi is a postdoctoral research fellow within Johanna Lampe's research group at Fred Hutch. Darya studies the nuanced connections between diet, gut epithelium, and gut microbiome in relation to colorectal cancer using high-dimensional approaches.