{"entity":{"id":"paper-conti-trans-ancestry-gwas-prostate-nat-genet-2021","kind":"paper","name":"Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction","aka":["Conti 2021","prostate polygenic risk score 269 variants","trans-ancestry prostate GWAS"],"tldr":"The largest genetic study of prostate cancer pooled 107,247 men with the disease and 127,006 without, across ancestries. It brought the number of known risk variants to 269 and showed that men of African ancestry carry, on average, more than twice the genetic risk score of men of European ancestry.","summary":"David Conti, Christopher Haiman, Rosalind Eeles and a very large consortium ran a multi-ancestry meta-analysis of prostate cancer genome-wide association studies and combined the resulting variants into a genetic risk score, then compared the distribution of that score across ancestry groups.\n\nThe finding that matters for policy is the last one. Prostate cancer incidence and mortality differ sharply by ancestry, and the argument about why has run for decades between biology and access to care. This paper supplies a measured component of the biological side: the mean genetic risk score is 2.18 times higher in men of African ancestry and 0.73 times that of European ancestry in men of East Asian ancestry. It does not settle the mortality question, which Dess and colleagues addressed by adjusting for access, but it does say that a screening programme whose entry criterion is age alone is using the wrong variable.","asOf":"2026-09-25","links":[{"label":"Nat Genet 2021","url":"https://doi.org/10.1038/s41588-020-00748-0"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33398198/"}],"tags":["prostate-evidence"],"related":["paper-dess-black-race-prostate-mortality-jama-oncol-2019","paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","idea-prev-prs-screening-start-age","idea-prev-mri-first-prostate-screening-prs","prostate-roadmap"],"cancers":["prostate"],"sections":["prevention","early-detection","diagnostics"],"technologies":["germline-testing"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["screening","polygenic-risk-score","other-cause-mortality"],"trials":[],"people":[],"bottlenecks":["b-hereditary-risk","b-early-detection","b-trial-diversity","b-global-access"],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":2021,"doi":"10.1038/s41588-020-00748-0","pmid":"33398198","authors":"Conti DV, Darst BF, Moss LC, et al.","paperType":"observational","findings":["A multi-ancestry meta-analysis of 107,247 cases and 127,006 controls identified 86 new risk variants, bringing the total to 269 known prostate cancer risk variants.","The top genetic risk score decile was associated with 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.","Men of African ancestry were estimated to have a mean genetic risk score 2.18 times higher than men of European ancestry (95 percent confidence interval 2.14 to 2.22).","Men of East Asian ancestry were estimated to have a mean genetic risk score 0.73 times that of men of European ancestry (0.71 to 0.76).","The authors concluded that germline variation contributes to population differences in prostate cancer risk and that the genetic risk score offers an approach to personalised risk prediction."],"whatItMeans":"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.","caveats":["A risk score built largely from European-ancestry discovery data, which is why its odds ratio is lower in men of African ancestry despite their higher mean score.","Association study design: the variants are markers of risk, not causes with known mechanisms.","A higher mean genetic risk score explains part of the difference in incidence and says nothing directly about differences in mortality, which are strongly influenced by access to care."],"changedPractice":false,"participants":234253},"route":"/key-papers/paper-conti-trans-ancestry-gwas-prostate-nat-genet-2021/","neighbours":{"paper":[{"id":"paper-dess-black-race-prostate-mortality-jama-oncol-2019","kind":"paper","name":"Association of Black race with prostate cancer-specific and other-cause mortality","route":"/key-papers/paper-dess-black-race-prostate-mortality-jama-oncol-2019/"},{"id":"paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","kind":"paper","name":"Inherited DNA-repair gene mutations in men with metastatic prostate cancer","route":"/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/"}],"idea":[{"id":"idea-prev-mri-first-prostate-screening-prs","kind":"idea","name":"MRI-first prostate screening with genetic pre-selection","route":"/ideas/idea-prev-mri-first-prostate-screening-prs/"},{"id":"idea-prostate-other-cause-mortality-as-a-reported-service-outcome","kind":"idea","name":"Report death from other causes as an outcome of the prostate cancer service, split by deprivation and ethnicity","route":"/ideas/idea-prostate-other-cause-mortality-as-a-reported-service-outcome/"},{"id":"idea-prev-prs-screening-start-age","kind":"idea","name":"Use a polygenic risk score to set when screening starts","route":"/ideas/idea-prev-prs-screening-start-age/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"cancer":[{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"early-detection","kind":"section","name":"Early Detection & Screening","route":"/fronts/early-detection/"},{"id":"prevention","kind":"section","name":"Prevention & Risk","route":"/fronts/prevention/"}],"technology":[{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"}],"term":[{"id":"other-cause-mortality","kind":"term","name":"Other-cause mortality","route":"/terms/other-cause-mortality/"},{"id":"polygenic-risk-score","kind":"term","name":"Polygenic risk score (PRS)","route":"/terms/polygenic-risk-score/"},{"id":"screening","kind":"term","name":"Screening","route":"/terms/screening/"}],"bottleneck":[{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/"},{"id":"b-global-access","kind":"bottleneck","name":"Most of the world has almost no cancer care","route":"/bottlenecks/b-global-access/"},{"id":"b-early-detection","kind":"bottleneck","name":"The hardest cancers are found late","route":"/bottlenecks/b-early-detection/"},{"id":"b-trial-diversity","kind":"bottleneck","name":"Trials do not represent the people who get cancer","route":"/bottlenecks/b-trial-diversity/"}],"journal":[{"id":"nature-genetics","kind":"journal","name":"Nature Genetics","route":"/journals/nature-genetics/"}]}}