{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:55:42Z","timestamp":1792760142461,"version":"4.5.0"},"reference-count":18,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,10]],"date-time":"2022-12-10T00:00:00Z","timestamp":1670630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background: Reversion mutations in BRCA1\/2, resulting in restoration of the open reading frame, have been identified as a mechanism of resistance to platinum-based chemotherapy or PARP inhibition. We sought to explore the incidence of BRCA1\/2 reversion mutations in different tumor types. Methods: We retrospectively analyzed molecular profiling results from primary and\/or metastatic tumor samples submitted by multiple institutions. The samples underwent DNA and RNA sequencing at a CLIA\/CAP-certified clinical lab. Reversion mutations were called only in patients whose available clinical records showed the use of PARP inhibitors or platinum agents prior to tumor profiling. Results: Reversion mutations were identified in 75 of 247,926 samples profiled across all tumor types. Among patients carrying pathogenic or likely pathogenic BRCA1\/2 mutations, reversion mutations in BRCA1\/2 genes were seen in ovarian cancer (OC) (30\/3424), breast cancer (BC) (27\/1460), endometrial cancer (4\/564), pancreatic cancer (2\/340), cholangiocarcinoma (2\/178), prostate cancer (5\/461), cervical cancer (1\/117), cancer of unknown primary (1\/244), bladder cancer (1\/300), malignant pleural mesothelioma (1\/10), and a neuroendocrine tumor of the prostate. We identified 22 reversion mutations in BRCA1 and 8 in BRCA2 in OC. In BC, we detected 6 reversion mutations in BRCA1 and 21 in BRCA2. We compared molecular profile results of 14 high-grade serous ovarian cancers (HGSOC) with reversion mutations against 87 control HGSOC with pathogenic BRCA1\/2 mutations without reversion mutations. Tumors with reversion mutations trended to have had lower ER expression (25% vs. 64%, p = 0.024, q = 0.82) and higher KDM6A mutation rate (15% vs. 0, p = 0.016, q = 0.82). Conclusions: We present one of the largest datasets reporting reversion mutations in BRCA1\/2 genes across various tumor types. These reversion mutations were rare; this may be because some patients may not have had repeat profiling post-treatment. Repeat tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.<\/jats:p>","DOI":"10.3390\/medicina58121818","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T02:15:33Z","timestamp":1670811333000},"page":"1818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["BRCA1\/2 Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents"],"prefix":"10.3390","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3395-894X","authenticated-orcid":false,"given":"Sourat","family":"Darabi","sequence":"first","affiliation":[{"name":"Hoag Family Cancer Institute, Newport Beach, CA 92663, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Braxton","sequence":"additional","affiliation":[{"name":"Hoag Family Cancer Institute, Newport Beach, CA 92663, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Xiu","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5468-1126","authenticated-orcid":false,"given":"Benedito A.","family":"Carneiro","sequence":"additional","affiliation":[{"name":"Legorreta Cancer Center, Brown University, Providence, RI 02912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Swensen","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel S.","family":"Antonarakis","sequence":"additional","affiliation":[{"name":"University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen V.","family":"Liu","sequence":"additional","affiliation":[{"name":"Georgetown University, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana R.","family":"McKay","sequence":"additional","affiliation":[{"name":"University of California San Diego Health, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Spetzler","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9577-8266","authenticated-orcid":false,"given":"Wafik S.","family":"El-Deiry","sequence":"additional","affiliation":[{"name":"Legorreta Cancer Center, Brown University, Providence, RI 02912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Demeure","sequence":"additional","affiliation":[{"name":"Hoag Family Cancer Institute, Newport Beach, CA 92663, USA"},{"name":"Translational Genomics Research Institute, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1158\/2159-8290.CD-19-1485","article-title":"Clinical BRCA1\/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy ResistanceBRCA Gene Reversions","volume":"10","author":"Pettitt","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.7150\/jca.65650","article-title":"Comprehensive Analysis of Somatic Reversion Mutations in Homologous Recombination Repair (HRR) Genes in A Large Cohort of Chinese Pan-cancer Patients","volume":"13","author":"Zong","year":"2022","journal-title":"J. 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