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We aimed to characterize germline pathogenic variants (PVs) in Spanish PCa patients and identify predictors of carrier status. We retrospectively analyzed 360 PCa patients referred for genetic counseling. Multigene panel testing of 13 cancer predisposition genes was performed. PV frequencies were compared with internal pseudo-controls and public population controls. Associations with age at diagnosis, clinical risk group, and family history (FH) were evaluated. Overall, 6.4% of patients carried a germline PV.\n                    <jats:italic>BRCA2<\/jats:italic>\n                    and\n                    <jats:italic>ATM<\/jats:italic>\n                    were the most frequently mutated genes (1.67% each), showing significant enrichment compared with all control groups.\n                    <jats:italic>TP53<\/jats:italic>\n                    and\n                    <jats:italic>PALB2<\/jats:italic>\n                    were also significantly associated with PCa risk. High-risk or metastatic disease, age\u2009&lt;\u200960 years, and FH of hereditary breast\/ovarian or Lynch syndrome-spectrum tumors were the best predictors for the presence of PV. Our findings suggest an unexpected major role for\n                    <jats:italic>TP53<\/jats:italic>\n                    and\n                    <jats:italic>PALB2<\/jats:italic>\n                    as key PCa susceptibility genes, reinforce the role of\n                    <jats:italic>BRCA2<\/jats:italic>\n                    and\n                    <jats:italic>ATM<\/jats:italic>\n                    , and question the role of\n                    <jats:italic>BRCA1<\/jats:italic>\n                    . Genetic testing may be most informative when focused on younger patients with non-low-risk disease and relevant FH.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-60564-0","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T15:55:48Z","timestamp":1783007748000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Germline pathogenic variants associated with prostate cancer susceptibility in a Spanish cohort: emergence of new key players"],"prefix":"10.1038","volume":"16","author":[{"given":"Camila","family":"Reeb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciela","family":"Ur\u00eda-Regojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Gonz\u00e1lez-Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Amil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Radu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Ben\u00edtez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Gomis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Blanco-Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Mireia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fermina","family":"L\u00f3pez-Grondona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Lorda-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Salgado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Isabel","family":"S\u00e1nchez-Barbero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saoud","family":"Swafiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Gimbernat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ram\u00edrez-Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e1n","family":"Husillos-Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"S\u00e1nchez-Encinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Gonz\u00e1lez-Enguita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Trujillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Ayuso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"M\u00ednguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Osorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"60564_CR1","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.eururo.2024.11.013","volume":"87","author":"EJ Schafer","year":"2025","unstructured":"Schafer, E. 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