{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T15:54:05Z","timestamp":1774972445926,"version":"3.50.1"},"reference-count":54,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Genetic alterations in <jats:italic>FGF\/FGFR<\/jats:italic> pathway are infrequent in gastrointestinal stromal tumors (GIST), with rare cases of quadruple wildtype GISTs harboring <jats:italic>FGFR1<\/jats:italic> gene fusions and mutations. Additionally, FGF\/FGFR overexpression was shown to promote drug resistance to kinase inhibitors in GISTs. However, <jats:italic>FGFR<\/jats:italic> gene fusions have not been directly implicated as a mechanism of drug resistance in GISTs. Herein, we report a patient presenting with a primary small bowel spindle cell GIST and concurrent peritoneal and liver metastases displaying an imatinib\u2010sensitive <jats:italic>KIT<\/jats:italic> exon 11 in\u2010frame deletion. After an initial 9\u2010month benefit to imatinib, the patient experienced intraabdominal peritoneal recurrence owing to secondary <jats:italic>KIT<\/jats:italic> exon 13 missense mutation and <jats:italic>FGFR4<\/jats:italic> amplification. Despite several additional rounds of tyrosine kinase inhibitors (TKI), the patient's disease progressed after 2\u2009years and presented with multiple peritoneal and liver metastases, including one pericolonic mass harboring secondary <jats:italic>KIT<\/jats:italic> exon 18 missense mutation, and a concurrent transverse colonic mass with a <jats:italic>FGFR2::TACC2<\/jats:italic> fusion and <jats:italic>AKT2<\/jats:italic> amplification. All tumors, including primary and recurrent masses, harbored an <jats:italic>MGA<\/jats:italic> c.7272\u2009T\u2009&gt;\u2009G (p.Y2424*) nonsense mutation and <jats:italic>CDKN2A\/CDKN2B\/MTAP<\/jats:italic> deletions. The transcolonic mass showed elevated mitotic count (18\/10 HPF), as well as significant decrease in CD117 and DOG1 expression, in contrast to all the other resistant nodules that displayed diffuse and strong CD117 and DOG1 immunostaining. The <jats:italic>FGFR2::TACC2<\/jats:italic> fusion resulted from a 742\u2009kb intrachromosomal inversion at the chr10q26.3 locus, leading to a fusion between exons 1\u201317 of <jats:italic>FGFR2<\/jats:italic> and exons 7\u201317 <jats:italic>TACC2<\/jats:italic>, which preserves the extracellular and protein tyrosine kinase domains of FGFR2. We present the first report of a multidrug\u2010resistant GIST patient who developed an <jats:italic>FGFR2<\/jats:italic> gene fusion as a secondary genetic event to the selective pressure of various TKIs. This case also highlights the heterogeneous escape mechanisms to targeted therapy across various tumor nodules, spanning from both KIT\u2010dependent and KIT\u2010independent off\u2010target activation pathways.<\/jats:p>","DOI":"10.1002\/gcc.23030","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T04:19:08Z","timestamp":1644985148000},"page":"412-419","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["<i><scp>FGFR2<\/scp>::<scp>TACC2<\/scp><\/i> fusion as a novel <scp>KIT<\/scp>\u2010independent mechanism of targeted therapy failure in a multidrug\u2010resistant gastrointestinal stromal tumor"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1139-2914","authenticated-orcid":false,"given":"Josephine K.","family":"Dermawan","sequence":"first","affiliation":[{"name":"Department of Pathology Memorial Sloan Kettering Cancer Center  New York New York 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William D.","family":"Tap","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9717-8205","authenticated-orcid":false,"given":"Cristina R.","family":"Antonescu","sequence":"additional","affiliation":[{"name":"Department of Pathology Memorial Sloan Kettering Cancer Center  New York New York 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