{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T09:16:37Z","timestamp":1760346997381,"version":"build-2065373602"},"reference-count":28,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cancer League Zurich","award":["Investigation of novel marker combinations to  predict response to immunotherapy in mucosal  melanoma"],"award-info":[{"award-number":["Investigation of novel marker combinations to  predict response to immunotherapy in mucosal  melanoma"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Mucosal melanoma can be driven by various driver mutations in genes such as NRAS, KIT, or KRAS. However, some cases present with only weak drivers, or lacking known oncogenic drivers, suggesting immunotherapy over targeted therapy. While resistance mechanisms to immunotherapy in cutaneous melanoma have been uncovered, including alterations in JAK1\/2, B2M, or STK11, a switch of oncogenic drivers under immunotherapy has not yet been observed. We report three cases of metastatic sinonasal melanoma that switched oncogenic drivers from KRAS, KIT, or no driver to NRAS during or after immunotherapy, thereby showing progressive disease. One of the cases presented with three spatially separate driver mutations in the primary tumor, whereas the NRAS clone persisted under immunotherapy. In comparison, three different control cases receiving radiotherapy only did not show a change of the detectable molecular drivers in their respective recurrences or metastases. In summary, these data provide an important rationale for longitudinal molecular testing, based on evidence for an unforeseen recurrent event of molecular driver switch to NRAS in progressing sinonasal melanoma. These findings provide the basis for further studies on a potential causal relation of emerging NRAS mutant clones and immunotherapy.<\/jats:p>","DOI":"10.3390\/cancers13112725","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T21:42:06Z","timestamp":1622497326000},"page":"2725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Who\u2019s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6874-9649","authenticated-orcid":false,"given":"Sandra N.","family":"Freiberger","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3695-8264","authenticated-orcid":false,"given":"Patrick","family":"Turko","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Zurich, 8058 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-3292","authenticated-orcid":false,"given":"Martin","family":"H\u00fcllner","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Nuclear Medicine, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2279-6906","authenticated-orcid":false,"given":"Reinhard","family":"Dummer","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Dermatology, University Hospital Zurich, 8058 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6150-6772","authenticated-orcid":false,"given":"Gr\u00e9goire B.","family":"Morand","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Department of Otolaryngology, Head and Neck Surgery, Sir Mortimer B. Davis\u2014Jewish General Hospital, McGill University, Montreal, QC H3T1E2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5902-9420","authenticated-orcid":false,"given":"Mitchell P.","family":"Levesque","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Dermatology, University Hospital Zurich, 8058 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8176-8358","authenticated-orcid":false,"given":"David","family":"Holzmann","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7043-3456","authenticated-orcid":false,"given":"Niels J.","family":"Rupp","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.critrevonc.2017.01.019","article-title":"Mucosal melanoma of the head and neck","volume":"112","author":"Ascierto","year":"2017","journal-title":"Crit. 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