{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:42:08Z","timestamp":1791387728537,"version":"4.3.3"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T00:00:00Z","timestamp":1720051200000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Individuals with germline pathogenic variants in BRCA1 or BRCA2 are at a high risk of breast and ovarian carcinomas with BRCA1\/2 deficiency and homologous recombination deficiency that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances, and genomic loss of heterozygosity. Malignancies with homologous recombination deficiency are more sensitive to platinum-based therapies and poly(ADP-ribose) polymerase inhibitors. We investigated the fraction of non\u2013breast or ovarian malignancies that have BRCA1\/2 deficiency and genomic instability features.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The full tumor history of a large, historical, clinic-based, consecutive cohort of 2965 individuals with germline pathogenic variants in BRCA1\/2 was retrieved from the Dutch nationwide pathology databank (Palga). In total, 169 non\u2013breast or ovarian malignancies were collected and analyzed using targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second-hit alterations and genomic instabilities indicative of homologous recombination deficiency, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>BRCA1\/2 deficiency was detected in 27% (21\/79) and 23% (21\/90) of 20 different types of non\u2013breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P\u2009&amp;lt;\u2009.001 and P\u2009&amp;lt;\u2009.001, respectively).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>BRCA1\/2 deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non\u2013breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. Evaluation of the effectiveness of poly(ADP-ribose) polymerase inhibitors in these individuals should be focused on tumors with a confirmed absence of a wild-type allele.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jnci\/djae160","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T21:48:13Z","timestamp":1719956893000},"page":"1904-1913","source":"Crossref","is-referenced-by-count":9,"title":["Genomic instability in non\u2013breast or ovarian malignancies of individuals with germline pathogenic variants in <i>BRCA1\/2<\/i>"],"prefix":"10.1093","volume":"116","author":[{"given":"Lisa","family":"Elze","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel S","family":"van der Post","sequence":"additional","affiliation":[{"name":"Department of Pathology, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet R","family":"Vos","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjen R","family":"Mensenkamp","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samhita","family":"Pamidimarri Naga","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliet E","family":"Hampstead","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"Oorsprong","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Hofste","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"Simons","sequence":"additional","affiliation":[{"name":"Department of Pathology, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris D","family":"Nagtegaal","sequence":"additional","affiliation":[{"name":"Department of Pathology, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2393-8141","authenticated-orcid":false,"given":"Nicoline","family":"Hoogerbrugge","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richarda M","family":"de Voer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-1474","authenticated-orcid":false,"given":"Marjolijn J L","family":"Ligtenberg","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud university medical center , Nijmegen,","place":["the Netherlands"]},{"name":"Department of Pathology, Radboud university medical center , Nijmegen,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,3]]},"reference":[{"issue":"11","key":"2024121020552135800_djae160-B1","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1200\/JCO.2006.09.1066","article-title":"Meta-analysis of BRCA1 and BRCA2 penetrance","volume":"25","author":"Chen","year":"2007","journal-title":"J Clin Oncol"},{"issue":"5182","key":"2024121020552135800_djae160-B2","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1126\/science.7545954","article-title":"A strong candidate for the breast and ovarian cancer susceptibility gene 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