{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T12:36:14Z","timestamp":1792499774000,"version":"4.5.0"},"reference-count":151,"publisher":"American Association for Cancer Research (AACR)","issue":"5","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":78,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA270108"],"award-info":[{"award-number":["R01CA270108"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U2CACA271894"],"award-info":[{"award-number":["U2CACA271894"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014039","name":"DOD Prostate Cancer Research Program","doi-asserted-by":"publisher","award":["W81XWH2210247"],"award-info":[{"award-number":["W81XWH2210247"]}],"id":[{"id":"10.13039\/100014039","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014039","name":"DOD Prostate Cancer Research Program","doi-asserted-by":"publisher","award":["W81XWH2210751"],"award-info":[{"award-number":["W81XWH2210751"]}],"id":[{"id":"10.13039\/100014039","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Newly diagnosed prostate cancers differ dramatically in mutational composition and lethality. The most accurate clinical predictor of lethality is tumor tissue architecture, quantified as tumor grade. To interrogate the evolutionary origins of prostate cancer heterogeneity, we analyzed 666 prostate tumor whole genomes. We identified a compendium of 223 recurrently mutated driver regions, most influencing downstream mutational processes and gene expression. We identified and validated individual germline variants that predispose tumors to acquire specific somatic driver mutations: these explain heterogeneity in disease presentation and ancestry differences. High-grade tumors have a superset of the drivers in lower-grade tumors, including increased frequency of BRCA2 and MYC mutations. Grade-associated driver mutations occur early in tumor evolution, and their earlier occurrence strongly predicts cancer relapse and metastasis. Our data suggest high- and low-grade prostate tumors both emerge from a common premalignant field, influenced by germline genomic context and stochastic mutation timing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This study uncovered 223 recurrently mutated driver regions using the largest cohort of prostate tumors to date. It reveals associations between germline SNPs, somatic drivers, and tumor aggression, offering significant insights into how prostate tumor evolution is shaped by germline factors and the timing of somatic mutations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-23-0882","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T10:44:07Z","timestamp":1739443447000},"page":"988-1017","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Germline and Somatic Origins of Prostate Cancer Heterogeneity"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1082-3871","authenticated-orcid":false,"given":"Takafumi N.","family":"Yamaguchi","sequence":"first","affiliation":[{"name":"1Ontario Institute for Cancer Research, Toronto, Canada."},{"name":"2Department of Human Genetics, University of California, Los Angeles, Los Angeles, California."},{"name":"3Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, California."},{"name":"4Institute for Precision Health, University of California, Los Angeles, Los Angeles, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2273-2099","authenticated-orcid":false,"given":"Kathleen E.","family":"Houlahan","sequence":"additional","affiliation":[{"name":"1Ontario Institute for Cancer Research, Toronto, Canada."},{"name":"2Department of Human Genetics, University of California, Los Angeles, Los Angeles, California."},{"name":"3Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, California."},{"name":"4Institute for Precision Health, University of California, Los Angeles, Los Angeles, California."},{"name":"5Department of Medical Biophysics, University of Toronto, Toronto, Canada."},{"name":"6Vector Institute, Toronto, Canada."},{"name":"7Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5174-4582","authenticated-orcid":false,"given":"Helen","family":"Zhu","sequence":"additional","affiliation":[{"name":"1Ontario Institute for Cancer Research, Toronto, Canada."},{"name":"5Department of Medical Biophysics, University of Toronto, Toronto, Canada."},{"name":"6Vector Institute, Toronto, Canada."},{"name":"8Princess Margaret Cancer Centre, University Health Network, Toronto, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8555-5528","authenticated-orcid":false,"given":"Natalie","family":"Kurganovs","sequence":"additional","affiliation":[{"name":"1Ontario Institute for Cancer Research, Toronto, Canada."},{"name":"8Princess Margaret Cancer Centre, University Health Network, Toronto, Canada."},{"name":"9Australian Prostate Cancer Research Centre 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