{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:55:43Z","timestamp":1792760143339,"version":"4.5.0"},"reference-count":34,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T00:00:00Z","timestamp":1701388800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007451","name":"Cell Science Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007451","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22ck0106872"],"award-info":[{"award-number":["JP22ck0106872"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K08829"],"award-info":[{"award-number":["23K08829"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008732","name":"Uehara Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tumor sensitivity to platinum (Pt)\u2010based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency\u2010causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1\/2 (<jats:italic>BRCA1\/2<\/jats:italic>) mutations; however, <jats:italic>BRCA1\/2<\/jats:italic> reversion mutations have not been comprehensively studied in pan\u2010cancer cohorts. We aimed to characterize <jats:italic>BRCA1\/2<\/jats:italic> reversion mutations in a large pan\u2010cancer cohort of Japanese patients by retrospectively analyzing sequencing data for <jats:italic>BRCA1\/2<\/jats:italic> pathogenic\/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell\u2010free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic <jats:italic>BRCA1<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20093) and <jats:italic>BRCA2<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20099) reversion mutations in breast (<jats:italic>n<\/jats:italic>\u2009=\u20094), ovarian\/fallopian tube\/peritoneal (<jats:italic>n<\/jats:italic>\u2009=\u20094), pancreatic (<jats:italic>n<\/jats:italic>\u2009=\u20092), prostate (<jats:italic>n<\/jats:italic>\u2009=\u20091), and gallbladder (<jats:italic>n<\/jats:italic>\u2009=\u20091) cancers. We identified 21 reversion events\u2014<jats:italic>BRCA1<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20093), <jats:italic>BRCA2<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u200918)\u2014including eight pure deletions, one single\u2010nucleotide variant, six multinucleotide variants, and six deletion\u2013insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than\u20091\u2009bp, suggesting microhomology\u2010mediated end\u2010join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP\u2010inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt\u2010based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and <jats:italic>BRCA1<\/jats:italic> reversion mutations had no history of either treatment. Although reversion mutations commonly occur in <jats:italic>BRCA<\/jats:italic>\u2010associated cancers, our findings suggest that reversion mutations due to Pt\u2010chemotherapy might be correlated with <jats:italic>BRCA1\/2<\/jats:italic>\u2010mediated tumorigenesis even in non\u2010<jats:italic>BRCA<\/jats:italic>\u2010associated histologies.<\/jats:p>","DOI":"10.1111\/cas.16033","type":"journal-article","created":{"date-parts":[[2023,12,2]],"date-time":"2023-12-02T16:50:48Z","timestamp":1701535848000},"page":"635-647","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["<i>BRCA1\/2<\/i> reversion mutations in a pan\u2010cancer cohort"],"prefix":"10.1111","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5162-7132","authenticated-orcid":false,"given":"Kohei","family":"Nakamura","sequence":"first","affiliation":[{"name":"Genomics Unit, Keio Cancer Center Keio University School of Medicine  Tokyo Japan"},{"name":"Department of Obstetrics and Gynecology Kumagaya General Hospital  Kumagaya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-8015","authenticated-orcid":false,"given":"Hideyuki","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Genomics Unit, Keio Cancer Center Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryutaro","family":"Kawano","sequence":"additional","affiliation":[{"name":"Genomics Unit, Keio Cancer Center Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marin","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Genomics Unit, Keio Cancer Center Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Aimono","sequence":"additional","affiliation":[{"name":"Genomics Unit, Keio Cancer Center Keio University School of Medicine  Tokyo Japan"},{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Genomics Unit, Keio Cancer Center Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology, Adachi Medical Center Tokyo Women's Medical University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Kojima","sequence":"additional","affiliation":[{"name":"Showa University Institute for Clinical Genetics and Genomics  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Niikura","sequence":"additional","affiliation":[{"name":"Department of Breast Oncology Tokai University School of Medicine  Isehara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Kawanishi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine Tokai University School of Medicine  Isehara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Tokai University Hospital  Isehara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Cancer Center Kagoshima University Hospital  Kagoshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Ueno","sequence":"additional","affiliation":[{"name":"Cancer Center Kagoshima University Hospital  Kagoshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Okuwaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Kitasato University School of Medicine  Sagamihara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4353-4382","authenticated-orcid":false,"given":"Jiichiro","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Division of Clinical Oncology, Department of Comprehensive Medicine, Research and Development Center for New Medical Frontiers Kitasato University School of Medicine  Sagamihara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetics University of Miyazaki Hospital  Miyazaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Masuda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8214-2242","authenticated-orcid":false,"given":"Tatsuyuki","family":"Chiyoda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Yamagami","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Communication Engineering Center, Electronic Systems Business Group Mitsubishi Electric Software Co., Ltd.  Amagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachio","family":"Nohara","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Communication Engineering Center, Electronic Systems Business Group Mitsubishi Electric Software Co., Ltd.  Amagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeki","family":"Tanishima","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Communication Engineering Center, Electronic Systems Business Group Mitsubishi Electric Software Co., Ltd.  Amagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5460-8703","authenticated-orcid":false,"given":"Hiroshi","family":"Nishihara","sequence":"additional","affiliation":[{"name":"Genomics Unit, Keio Cancer Center Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03445"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03443"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.1703"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdq628"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2019.07.008"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1382-1"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06548"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0715"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-17-0098"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.10.470"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-6657-2"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1485"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-2933"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0734"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06633"},{"key":"e_1_2_12_17_1","unstructured":"U.S. Food and Drug Administration.FoundationOne CDx\u2010 P170019\/S014 technical information. Accessed February 18 2022https:\/\/www.accessdata.fda.gov\/cdrh_docs\/pdf17\/P170019S006C.pdf"},{"key":"e_1_2_12_18_1","unstructured":"U.S. Food and Drug Administration.FoundationOne Liquid CDx (F1 LiquidCDx)\u2010 P190032\/S010 technical information. Accessed June 08 2023https:\/\/www.accessdata.fda.gov\/cdrh_docs\/pdf19\/P190032S010C.pdf"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/2469523"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20880"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt755"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky653"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.5985"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14184"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34109-8"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.15.1310"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.0476"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19406-4"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01230"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002409"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng747"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.48"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(02)00325-X"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0088"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.34.2980"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.16033","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T07:22:13Z","timestamp":1710228133000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.16033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12]]},"references-count":34,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,2]]}},"alternative-id":["10.1111\/cas.16033"],"URL":"https:\/\/doi.org\/10.1111\/cas.16033","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12]]},"assertion":[{"value":"2023-09-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}