{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T16:41:46Z","timestamp":1768322506479,"version":"3.49.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["12995"],"award-info":[{"award-number":["12995"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The identification of causal\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision\u2010making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    PVs cluster in high\u2010grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009946 EOCs revealed\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    PVs in 125 samples (13%), only eight of which were found in non\u2010HGSOC histotypes. Specifically,\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    PVs were identified in high\u2010grade endometrioid (3\/20; 15%), low\u2010grade endometrioid (1\/40; 2.5%), low\u2010grade serous (3\/67; 4.5%), and clear cell (1\/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re\u2010evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight \u2018anomalous\u2019 cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first \u2018anomalous\u2019 non\u2010HGSOC with a\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    PV proved to be a misdiagnosed HGSOC. Next, germline\n                    <jats:italic>BRCA2<\/jats:italic>\n                    variants, found in two p53\u2010abnormal high\u2010grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53\u2010wildtype low\u2010grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    wildtype allele, suggestive of non\u2010causal secondary passenger variants. We conclude that likely causal\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    variants are present in high\u2010grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype\u2010directed sequencing. Furthermore, in\u2010depth functional analysis of tumours harbouring\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    variants combined with detailed revision of cancer histotypes can serve as a model in other\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    \u2010related cancers. \u00a9 2023 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6218","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T07:34:51Z","timestamp":1697614491000},"page":"137-146","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Causality and functional relevance of\n                    <scp>\n                      <i>BRCA1<\/i>\n                    <\/scp>\n                    and\n                    <scp>\n                      <i>BRCA2<\/i>\n                    <\/scp>\n                    pathogenic variants in non\u2010high\u2010grade serous ovarian carcinomas"],"prefix":"10.1002","volume":"262","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7399-6804","authenticated-orcid":false,"given":"CJH","family":"Kramer","sequence":"first","affiliation":[{"name":"Department of Pathology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Lanjouw","sequence":"additional","affiliation":[{"name":"Department of Epidemiology University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Ruano","sequence":"additional","affiliation":[{"name":"Department of Pathology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"ter Elst","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Santandrea","sequence":"additional","affiliation":[{"name":"Pathology Unit, Azienda USL\u2010IRCCS di Reggio Emilia  Reggio Emilia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N","family":"Solleveld\u2010Westerink","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"AH","family":"van der Hout","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"CD","family":"de Kroon","sequence":"additional","affiliation":[{"name":"Department of Gynecology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"van Wezel","sequence":"additional","affiliation":[{"name":"Department of Pathology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"LPV","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Groningen, University Medical Center Groningen  Groningen The 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