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A single number adding up hundreds of common, individually tiny genetic differences to say whether a man's inherited risk of prostate cancer is above or below average. It is not a test for a faulty gene like BRCA2, and it says nothing about how aggressive a cancer would be.
A polygenic risk score is the weighted sum of the risk alleles a person carries across a set of common single nucleotide polymorphisms identified by genome-wide association studies, each of which shifts risk by a fraction of a percent. It is a population ranking device: it places a man in a percentile of inherited susceptibility. It is categorically different from a germline test for a rare high-penetrance variant such as BRCA2 or a mismatch repair gene, which names a single fault with a large effect and consequences for relatives.
Prostate cancer has the best-developed score of any common cancer, and the biggest ancestry problem. Conti, Haiman and Eeles ran a multi-ancestry meta-analysis of 107,247 cases and 127,006 controls, identified 86 new risk variants for a total of 269, and built a score from them. The top decile carried odds ratios from 5.06 (95 percent confidence interval 4.84 to 5.29) in men of European ancestry to 3.74 (3.36 to 4.17) in men of African ancestry, and the mean score was 2.18 times higher in men of African ancestry (2.14 to 2.22) and 0.73 times that of European ancestry in men of East Asian ancestry (0.71 to 0.76). The discovery data were largely European, which is why the score discriminates least well in the group with the highest mean risk.
The United Kingdom has tested it prospectively. BARCODE1 recruited men aged 55 to 69 through primary care, derived a score from 130 variants using saliva DNA, and invited those at or above the 90th percentile for multiparametric magnetic resonance imaging and transperineal biopsy irrespective of prostate-specific antigen. Of 40,292 invited, 6,393 had a score calculated, 745 (11.7 percent) were in the top decile and 468 were screened; prostate cancer was found in 187 (40.0 percent), of whom 103 had disease of intermediate risk or higher by 2024 NCCN criteria, and 74 of those 103 would not have been detected by the current United Kingdom pathway of raised prostate-specific antigen followed by magnetic resonance imaging. The trial had no comparator arm, which is the basis of the main criticism: standardised to 10,000 men tested, Sud and Vickers calculated that BARCODE1 biopsied more men (704 against 386 and 338), found more low-grade cancers (126 against 103 and 41) and found fewer high-grade cancers (155 against 178 and 165) than the contemporaneous Goteborg-2 and ProScreen trials, which risk-stratify with magnetic resonance imaging and blood markers. The open question is therefore not whether a score can find cancer but whether it finds the cancer that matters, and the current evidence is that it does not preferentially find aggressive disease.
Showing the technology this term belongs to: Polygenic risk scores for cancer.
This is the paper Europe PMC returns for registry id ISRCTN94604465 with the most citations, so it is the natural first reading for anyone following the trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
The evidence base for setting the age at which screening starts by risk rather than by birthday. It is also a warning: the same score performs differently across ancestries, so a risk model built and validated in European cohorts will under-serve the men at highest risk.
The disparity in prostate cancer death among Black men in the United States is, stage for stage and treatment for treatment, largely a disparity in getting standard care rather than in tumour biology. The disparity that survives equal access is in dying of everything else, which is the part a cancer service is least organised to fix and most able to measure.
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Shares Lead time, and lead-time bias, Number needed to screen (and number needed to diagnose), PSA and MRI-first prostate cancer screening, Overdiagnosis and the tags gu, prostate-glossary.
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Shares Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction, Association of Black race with prostate cancer-specific and other-cause mortality, Localised prostate cancer, intermediate risk, Localised prostate cancer, very low and low risk and the tags gu, prostate-glossary.
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Shares PSA (prostate-specific antigen), Localised prostate cancer, high and very high risk, Prostate cancer and the tags gu, prostate-glossary.
Shares Localised prostate cancer, high and very high risk, The hardest cancers are found late, Prostate cancer and the tags gu, prostate-glossary.
Shares Localised prostate cancer, high and very high risk, Prostate cancer and the tags gu, prostate-glossary.