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We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer\u2010gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A\/M melanomas. Using novel pre\u2010clinical models of A\/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A\/M melanomas. Other alterations, including <jats:italic>MYC<\/jats:italic> and <jats:italic>CRKL<\/jats:italic> amplifications, were unique to A\/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src\/ABL inhibitor dasatinib, respectively. We further identified new, actionable A\/M\u2010specific alterations, including an inactivating <jats:italic>NF2<\/jats:italic> fusion in a mucosal melanoma responsive to dasatinib <jats:italic>in vivo<\/jats:italic>. Our study highlights new molecular differences between cutaneous and A\/M melanomas, and across different anatomic sites within A\/M, which may change clinical testing and treatment paradigms for these rare melanomas.<\/jats:p>","DOI":"10.1002\/ijc.35087","type":"journal-article","created":{"date-parts":[[2024,7,13]],"date-time":"2024-07-13T01:14:36Z","timestamp":1720833276000},"page":"1792-1807","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling"],"prefix":"10.1002","volume":"155","author":[{"given":"Jacqueline A.","family":"Turner","sequence":"first","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Van Gulick","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"},{"name":"Center for Rare Melanomas, Department of Medicine University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"},{"name":"Center for Rare Melanomas, Department of Medicine University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tariq","family":"Mughal","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology Tufts University Cancer Center  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Tobin","sequence":"additional","affiliation":[{"name":"Center for Rare Melanomas, Department of Medicine University of Colorado Anschutz Medical Campus  Aurora Colorado USA"},{"name":"Department of Surgery University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan L.","family":"MacBeth","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"},{"name":"Center for Rare Melanomas, Department of Medicine University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blair","family":"Holman","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"},{"name":"Center for Rare Melanomas, Department of Medicine University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Classon","sequence":"additional","affiliation":[{"name":"Foundation Medicine Inc.  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