{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T16:11:06Z","timestamp":1778861466698,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,10]]},"group-title":"Genetic and Genomic Medicine","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Risk stratification for prostate cancer (PCa) progression or aggressiveness is often based on clinicopathologic features, some of which may be influenced by genetic factors. We developed a novel, germline polygenic risk score (PRSagg) to predict likelihood of developing aggressive PCa.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    PRSagg was developed using data from 38,688 patients with PCa (case-only analysis) from the Million Veteran Program (MVP) through a genome-wide search for variants associated with PCa grade group at diagnosis. We tested associations of PRSagg with grade group using the entire MVP dataset using the .632 bootstrap method. In an MVP cohort with localized PCa that was initially monitored without treatment, we tested PRSagg for association with unfavorable outcomes (subsequent development of grade group 4-5, metastasis, and\/or biochemical recurrence after definitive treatment). We performed external validation in data from patients in the PRACTICAL Consortium (n=45,214) and from participants in the ProtecT randomized trial who underwent active monitoring (n=316). Odds ratios (ORs) were calculated per standard deviation (SD) increase with 95% confidence intervals, while adjusting for age, genetic ancestry, a previously developed polygenic score for risk of PCa (PHS601), and a polygenic score for benign elevated prostate-specific antigen (PRS\n                    <jats:sub>PSA<\/jats:sub>\n                    ). For the outcome of metastasis, we additionally adjusted for PSA at diagnosis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In the MVP training dataset, PRSagg (172 variants) was associated with higher grade group at diagnosis (OR = 1.53 [1.51-1.56]) and with increased risk of unfavorable outcomes during monitoring (OR = 1.13 [1.09-1.18]). These findings were confirmed in the external datasets. PRSagg was associated with greater odds of higher grade group at diagnosis (OR = 1.09 [1.06-1.11]). Among ProtecT participants undergoing active monitoring, PRSagg was associated with higher risk of metastasis (OR = 2.15 [1.02-3.88]). Among MVP participants with high polygenic risk of developing any PCa, the risk of aggressive disease was highest in men with high PRSagg and low genetic risk of PSA elevation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Among men who develop PCa, a weighted sum of common germline variants (PRSagg) is independently associated with PCa aggressiveness. These findings may inform future study of germline influence on tumor evolution and risk-stratified intensity of active surveillance.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.07.26352488","type":"posted-content","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T23:15:14Z","timestamp":1778454914000},"source":"Crossref","is-referenced-by-count":0,"title":["Germline polygenic score for prostate cancer aggressiveness"],"prefix":"10.64898","author":[{"given":"George","family":"Xu","sequence":"first","affiliation":[{"name":"Research Service, VA San Diego Healthcare System, San Diego, CA, USA"},{"name":"Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roshan","family":"Karunamuni","sequence":"additional","affiliation":[{"name":"Research Service, VA San Diego Healthcare System, San Diego, CA, USA"},{"name":"Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna M","family":"Dornisch","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles A","family":"Brunette","sequence":"additional","affiliation":[{"name":"VA Boston Healthcare System, Boston, MA, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan E","family":"Danowski","sequence":"additional","affiliation":[{"name":"VA Boston Healthcare System, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heena","family":"Desai","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Dochtermann","sequence":"additional","affiliation":[{"name":"Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isla P","family":"Garraway","sequence":"additional","affiliation":[{"name":"Division of Urology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA"},{"name":"Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard L","family":"Hauger","sequence":"additional","affiliation":[{"name":"Research Service, VA San Diego Healthcare System, San Diego, CA, USA"},{"name":"Center for Behavior Genetics of Aging, School of Medicine, UC San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam S","family":"Kibel","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Department of Urology, Mass General Brigham, Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0108-2127","authenticated-orcid":false,"given":"Julie A","family":"Lynch","sequence":"additional","affiliation":[{"name":"VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System, Salt Lake City, UT, USA"},{"name":"Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saiju","family":"Pyarajan","sequence":"additional","affiliation":[{"name":"Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brent S","family":"Rose","sequence":"additional","affiliation":[{"name":"Research Service, VA San Diego Healthcare System, San Diego, CA, USA"},{"name":"Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig C","family":"Teerlink","sequence":"additional","affiliation":[{"name":"VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System, Salt Lake City, UT, USA"},{"name":"Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4461-3568","authenticated-orcid":false,"given":"Ole A","family":"Andreassen","sequence":"additional","affiliation":[{"name":"Center for Precision Psychiatry, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anders M","family":"Dale","sequence":"additional","affiliation":[{"name":"Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Radiology, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA"},{"name":"Hal\u0131c\u0131o\u011flu Data Science Institute, University of California San Diego, La Jolla, California, USA"},{"name":"NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny L","family":"Donovan","sequence":"additional","affiliation":[{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Freddie","family":"Hamdy","sequence":"additional","affiliation":[{"name":"Nuffield Department of Surgical Sciences, University of 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