{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:18:45Z","timestamp":1791357525146,"version":"4.3.1"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>BRCA2<\/jats:italic> is a causal gene for hereditary breast and ovarian cancer (HBOC) syndrome. However, its association with other cancers and interplay with polygenic scores (PGS) remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An observational cohort study for the diagnosis of various cancers in the UK Biobank (UKB, <jats:italic>N<\/jats:italic>\u2009=\u2009453,541) were recruited at ages of 40\u201369\u2009years Association of germline pathogenic variants (PVs) in <jats:italic>BRCA2<\/jats:italic> and published cancer\u2010specific PGS with cancer risk was tested using Cox proportional hazards model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The median age and interquartile range (IQR) of participants at the analysis was 58.34 (50.60\u201363.74)\u2009years. Carriers of <jats:italic>BRCA2<\/jats:italic> PVs (<jats:italic>N<\/jats:italic>\u2009=\u20091629) had a significantly increased risk for four core HBOC\u2010associated cancers (breast, ovarian, pancreatic, and prostate) and six additional types of cancer (lung, oral, small intestine, larynx, liver, and mesothelioma), hazard ratio (HR) &gt;\u20092.37, all <jats:italic>p<\/jats:italic>s\u2009&lt;\u20090.001. For eight cancers where cancer\u2010specific PGS is available, each PGS was significantly associated with its respective cancer risk and independent of <jats:italic>BRCA2<\/jats:italic>, HR\u2009&gt;\u20091.25 for 1\u2009unit increase in standard deviation, all <jats:italic>p<\/jats:italic>s\u2009&lt;\u20090.001. For female breast and prostate cancer, a significant interaction between <jats:italic>BRCA2<\/jats:italic> and PGS was found (HR\u2009&lt;\u20090.83, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05); the effect of PGS on cancer risk was weaker in carriers than noncarriers. The probability of cancer by age 75\u2009years (P<jats:sub>75<\/jats:sub>) for these 10 cancers increased with higher PGS deciles in both carriers and noncarriers. For several cancers, the P<jats:sub>75<\/jats:sub> in carriers with the lowest PGS decile was lower than that of noncarriers with the highest PGS decile.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>BRCA2<\/jats:italic> PVs increase risk beyond core HBOC cancers and their risks are modified by cancer\u2010specific PGS. These results suggest that genetic counseling of <jats:italic>BRCA2<\/jats:italic> PV carriers may extend to cancers beyond core HBOC syndrome and incorporate cancer\u2010specific PGS in estimating their penetrance.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.70990","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T04:40:49Z","timestamp":1749012049000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Estimating Cancer Penetrance in Carriers of <scp><i>BRCA2<\/i><\/scp> Pathogenic Variants Using Cancer\u2010Specific Polygenic Scores"],"prefix":"10.1002","volume":"14","author":[{"given":"Brendan","family":"Prassas","sequence":"first","affiliation":[{"name":"Program for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health)  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuqing","family":"Shi","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health)  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy","family":"Tran","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health)  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wei","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health)  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi\u2010Hsiung","family":"Wang","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health)  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9038-7014","authenticated-orcid":false,"given":"Andrew S.","family":"Rifkin","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health)  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle","family":"Ashworth","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health)  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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