{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:28:51Z","timestamp":1790659731344,"version":"4.1.0"},"reference-count":64,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30\u2010CA008748"],"award-info":[{"award-number":["P30\u2010CA008748"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P50 CA247749 01"],"award-info":[{"award-number":["P50 CA247749 01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K12 CA184746"],"award-info":[{"award-number":["K12 CA184746"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009845","name":"Ovarian Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009845","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":[[2022,8]]},"abstract":"Abstract<\/jats:title>Clear cell carcinoma (CCC) of the cervix (cCCC) is a rare and aggressive type of human papillomavirus (HPV)\u2010negative cervical cancer with limited effective treatment options for recurrent or metastatic disease. Historically, CCCs of the lower genital tract were associated with in utero<\/jats:italic> diethylstilbestrol exposure; however, the genetic landscape of sporadic cCCCs remains unknown. Here we sought to define the molecular underpinning of cCCCs. Using a combination of whole\u2010exome, targeted capture, and RNA\u2010sequencing, we identified pathogenic genetic alterations in the Hippo signaling pathway in 50% (10\/20) of cCCCs, including recurrent WWTR1<\/jats:italic> S89W somatic mutations in 40% (4\/10) of the cases harboring mutations in the Hippo pathway. Irrespective of the presence or absence of Hippo pathway genetic alterations, however, all primary cCCCs analyzed in this study (n<\/jats:italic>\u2009=\u200920) harbored features of Hippo pathway deregulation at the transcriptomic and protein levels. In vitro<\/jats:italic> functional analysis revealed that expression of the WWTR1<\/jats:italic> S89W mutation leads to reduced binding of TAZ to 14\u20103\u20103, promoting constitutive nuclear translocation of TAZ and Hippo pathway repression. WWTR1<\/jats:italic> S89W expression was found to lead to acquisition of oncogenic behavior, including increased proliferation, migration, and colony formation in vitro<\/jats:italic> as well as increased tumorigenesis in vivo<\/jats:italic>, which could be reversed by targeted inhibition of the TAZ\/YAP1 complex with verteporfin. Finally, xenografts expressing WWTR1 S89W displayed a shift in tumor phenotype, becoming more infiltrative as well as less differentiated, and were found to be composed of cells with conspicuous cytoplasmic clearing as compared to controls. Our results demonstrate that Hippo pathway alterations are likely drivers of cCCCs and likely contribute to the clear cell phenotype. Therapies targeting this pathway may constitute a new class of treatment for these rare, aggressive tumors. \u00a9 2022 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5910","type":"journal-article","created":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T08:02:43Z","timestamp":1649750563000},"page":"635-649","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Recurrent WWTR1<\/i>S89W<\/scp> mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix"],"prefix":"10.1002","volume":"257","author":[{"given":"Sarah H","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais","family":"Basili","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Higinio","family":"Dopeso","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Da Cruz Paula","sequence":"additional","affiliation":[{"name":"Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"},{"name":"Department of Pathology Fudan University Shanghai Cancer Center Shanghai PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirin","family":"Issa Bhaloo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fresia","family":"Pareja","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edaise M","family":"da Silva","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier","family":"Selenica","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajmohan","family":"Murali","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Chan","sequence":"additional","affiliation":[{"name":"Molecular Cytology Core Facility Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Derakhshan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Maroldi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etta","family":"Hanlon","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Gil","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Oncoclinicas Institute for Research and Education Sao Paulo Brazil"},{"name":"Federal University of Rio de Janeiro Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Roberto","family":"Lapa e Silva","sequence":"additional","affiliation":[{"name":"Federal University of Rio de Janeiro Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadeem R","family":"Abu\u2010Rustum","sequence":"additional","affiliation":[{"name":"Department of Surgery Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitriy","family":"Zamarin","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarat","family":"Chandarlapaty","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY USA"},{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathleen","family":"Matrai","sequence":"additional","affiliation":[{"name":"Department of Pathology Weill Cornell Medical Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju\u2010Yoon","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Pathology, St Michael's Hospital Unity Health Toronto Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2969-3173","authenticated-orcid":false,"given":"Jorge S","family":"Reis\u2010Filho","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay J","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9927-1270","authenticated-orcid":false,"given":"Britta","family":"Weigelt","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.13995"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-019-02601-0"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197104222841604"},{"key":"e_1_2_8_5_1","first-page":"85","article-title":"Selected item from the FDA drug bulletin\u2010november 1971: diethylstilbestrol contraindicated in pregnancy","volume":"116","year":"1972","journal-title":"Calif Med"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1800097"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001863"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19960201)77:3<507::AID-CNCR12>3.0.CO;2-8"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21386"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.03.020"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04128-5"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13806-x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3096"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05886-y"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2014.12.006"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djy216"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0321"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbs017"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw520"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2203"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-019-0334-5"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.09.033"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt445"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003118"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2004-5-10-r80"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.42"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.11.006"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.035"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijgo.12969"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1008433"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.06.007"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1602907"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.10.001"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.10.044"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.014"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1141-0"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008468"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-60143-x"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2015.05.065"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2221"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2303"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2018.51.3.015"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00049"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2019.10.005"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10137"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pdpdt.2010.12.001"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2014.95"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13138"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.264234.115"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2008.04.012"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01874-07"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4745"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16430"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.692285"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03781-2"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1097\/IGC.0b013e31828c8619"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2017.6180"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0151"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.022"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.8"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-3044"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5910","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.5910","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5910","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T09:47:57Z","timestamp":1761040077000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.5910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,20]]},"references-count":64,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1002\/path.5910"],"URL":"https:\/\/doi.org\/10.1002\/path.5910","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,20]]},"assertion":[{"value":"2021-11-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}