{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T06:51:28Z","timestamp":1783234288955,"version":"3.54.6"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology CR"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adult\u2010type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord\u2010stromal tumors and 2\u20135% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one\u2010third of patients relapse between 4 and 8\u2009years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (&gt;95%) harbor a somatic mutation in <jats:italic>FOXL2<\/jats:italic> (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides <jats:italic>FOXL2<\/jats:italic> C402G in aGCTs that could explain the clinical diversity of this disease. Whole\u2010genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon\u2010based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. <jats:italic>KMT2D<\/jats:italic> inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor <jats:italic>WNK2<\/jats:italic> and nonsense mutations in <jats:italic>PIK3R1<\/jats:italic> and <jats:italic>NLRC5<\/jats:italic>, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle\u2010related genes <jats:italic>TP53<\/jats:italic>, <jats:italic>CDKN2D<\/jats:italic>, and <jats:italic>CDK1<\/jats:italic>. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the <jats:italic>FOXL2<\/jats:italic> C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the <jats:italic>FOXL2<\/jats:italic> C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the <jats:italic>FOXL2<\/jats:italic> C402G mutation.<\/jats:p>","DOI":"10.1002\/cjp2.198","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T01:08:28Z","timestamp":1610672908000},"page":"243-252","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Adult\u2010type granulosa cell tumor of the ovary: a <scp><i>FOXL2<\/i><\/scp>\u2010centric disease"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1639-9971","authenticated-orcid":false,"given":"Jessica A","family":"Pilsworth","sequence":"first","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"},{"name":"Department of Medical Genetics University of British Columbia  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1523-9351","authenticated-orcid":false,"given":"Dawn R","family":"Cochrane","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha J","family":"Neilson","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahar H","family":"Moussavi","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asl\u0131 D","family":"Munzur","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Senz","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Kan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Zareian","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Bashashati","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of British Columbia  Vancouver BC Canada"},{"name":"School of Biomedical Engineering University of British Columbia  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Keul","sequence":"additional","affiliation":[{"name":"Department of Women's Health T\u00fcbingen University Hospital  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Staebler","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology T\u00fcbingen University Hospital  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah S","family":"van Meurs","sequence":"additional","affiliation":[{"name":"Department of Gynecology Center for Gynecologic Oncology Amsterdam, Academic Medical Center  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo M","family":"Horlings","sequence":"additional","affiliation":[{"name":"Department of Pathology The Netherlands Cancer Institute \u2013 Antoni van Leeuwenhoek  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Kommoss","sequence":"additional","affiliation":[{"name":"Department of Women's Health T\u00fcbingen University Hospital  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich","family":"Kommoss","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Medizin Campus Bodensee  Friedrichshafen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Oliva","sequence":"additional","affiliation":[{"name":"Department of Pathology Massachusetts General Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anniina EM","family":"F\u00e4rkkil\u00e4","sequence":"additional","affiliation":[{"name":"Research Program for Systems Oncology University of Helsinki and Helsinki University Hospital  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7889-8250","authenticated-orcid":false,"given":"Blake","family":"Gilks","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of British Columbia  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G","family":"Huntsman","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology British Columbia Cancer Research Centre  Vancouver BC Canada"},{"name":"Department of Pathology and Laboratory Medicine University of British Columbia  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2011-0014"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-3952(22)04460-X"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.10.019"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12917"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2017.1294760"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/IGC.0000000000000304"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.241"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/IGC.0b013e3182a57fb4"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2010.145"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0902542"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e31820a406c"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007988"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djw134"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2011.10.015"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2015.05.011"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.3802\/jgo.2011.22.3.188"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-018-0007-9"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-18-0359"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04950-x"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-0514-3"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12051308"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3849"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-4608(96)00077-5"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2004.12.014"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1283-0"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104726"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700683104"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1215\/15228517-2008-096"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds405"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.312"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.07.014"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2013.88"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-020-05253-5"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2018.11.024"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2016.03.006"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-0104"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-0259"}],"container-title":["The Journal of Pathology: Clinical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cjp2.198","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cjp2.198","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cjp2.198","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T19:25:22Z","timestamp":1760297122000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cjp2.198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,11]]},"references-count":37,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1002\/cjp2.198"],"URL":"https:\/\/doi.org\/10.1002\/cjp2.198","archive":["Portico"],"relation":{},"ISSN":["2056-4538","2056-4538"],"issn-type":[{"value":"2056-4538","type":"print"},{"value":"2056-4538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,11]]},"assertion":[{"value":"2020-06-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}