{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:42:04Z","timestamp":1781660524235,"version":"3.54.5"},"reference-count":12,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T00:00:00Z","timestamp":1695427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health and Family Planning Commission","doi-asserted-by":"publisher","award":["2020YJZX0202"],"award-info":[{"award-number":["2020YJZX0202"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health and Family Planning Commission","doi-asserted-by":"publisher","award":["SHDC12020108"],"award-info":[{"award-number":["SHDC12020108"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008750","name":"Shanghai ShenKang Hospital Development Center","doi-asserted-by":"publisher","award":["2020YJZX0202"],"award-info":[{"award-number":["2020YJZX0202"]}],"id":[{"id":"10.13039\/501100008750","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008750","name":"Shanghai ShenKang Hospital Development Center","doi-asserted-by":"publisher","award":["SHDC12020108"],"award-info":[{"award-number":["SHDC12020108"]}],"id":[{"id":"10.13039\/501100008750","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ovarian cancer is the leading cause of gynecologic cancer-related death, and PARP inhibitors (PARPis) are becoming a promising treatment option, as demonstrated by recent clinical trials. After PARPi exposure, somatic reversion mutations in the homologous recombination genes may be a mechanism of PARPi resistance in ovarian carcinoma. We present an ovarian cancer case of a 61-year-old woman, who underwent routine tumor reduction surgery followed by platinum and PARPis. She demonstrated a good response to PARPis for 15 months before recurrence and secondary tumor reduction surgery. However, post-surgery platinum and PARPi treatment only kept the disease stable for 5 months. A potential molecular mechanism for PARPi resistance was investigated using next-generation sequencing, immunohistochemical (IHC) staining, and other functional assays. A germline RAD51D loss-of-function mutation was found in the reported case (LRG_516t1:c.270_271dup p1:p.(Lys91fs*13)). Subsequently, a secondary mutation (LRG_516t1:c.271_282 del) was identified in the same locus of the germline duplication in the post-progression biopsies and ctDNA. The IHC staining supported low expression of RAD51D in the initial tumor tissue, but the expression was restored after the correction of the open reading frame by the secondary mutation. The in vitro results supported that the loss-of-function mutation of RAD51D was the basis for the initial response to the platinum and PARPi therapy, while the newly acquired reversion mutation could be attributed to the observed PARPi resistance. An acquired mutation can reverse a loss-of-function change in RAD51D and can result in PARPi resistance in a hereditary ovarian cancer patient. Liquid biopsy could be considered for longitudinal monitoring in ovarian patients under PARPi-based therapy, which can identify acquired resistant mutations earlier and facilitate precision management.<\/jats:p>","DOI":"10.3390\/ijms241914476","type":"journal-article","created":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T10:36:26Z","timestamp":1695551786000},"page":"14476","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["RAD51D Secondary Mutation-Mediated Resistance to PARP-Inhibitor-Based Therapy in HGSOC"],"prefix":"10.3390","volume":"24","author":[{"given":"Jing","family":"Xu","sequence":"first","affiliation":[{"name":"Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Dai","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Gao","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranran","family":"Chai","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-6500","authenticated-orcid":false,"given":"Chong","family":"Lu","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Yu","sequence":"additional","affiliation":[{"name":"Central Clinical School, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Kang","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congjian","family":"Xu","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"280","DOI":"10.3322\/caac.21559","article-title":"Epithelial ovarian cancer: Evolution of management in the era of precision medicine","volume":"69","author":"Lheureux","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/S1470-2045(16)30376-X","article-title":"Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: An updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial","volume":"17","author":"Ledermann","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1093\/annonc\/mdz192","article-title":"A decade of clinical development of PARP inhibitors in perspective","volume":"30","author":"Mateo","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/s41580-019-0152-0","article-title":"DNA double-strand break repair-pathway choice in somatic mammalian cells","volume":"20","author":"Scully","year":"2019","journal-title":"Nat. Rev. Mol. 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