title: Novel somatic KIT exon 8 mutation with dramatic response to imatinib in a patient with mucosal melanoma: a case report.
abstract: Primary mucosal melanomas represent ∼1.3% of all cases of melanoma diagnosed in the USA. The sinonasal location is the most common primary site. Mutations in the KIT gene occur in 10-22% of mucosal melanomas. Tumor response to imatinib mesylate has been reported in about half of the patients with tumors harboring KIT mutations. Responses are almost exclusively restricted to tumors with mutations in KIT exon 9 or 11. We report a case of a patient with a sinonasal mucosal melanoma with a novel exon 8 mutation (C443S) who had marked initial response to imatinib. Somatic exon 8 KIT mutations have not been previously reported in mucosal melanoma or in other human solid tumors; however, such mutations have been reported in canine and feline mast cell tumors. Protein transcripts from exon 8 play an important role in the structural and functional integrity of the extracellular domain of KIT. In preclinical studies, a mutation in exon 8 led to autophosphorylation, independent of KIT ligand, and constitutive activation of the tyrosine kinase. This biology may explain the successful application of imatinib in animals with tumors harboring exon 8 KIT mutations and in our patient with mucosal melanoma. This report expands the population of patients with melanoma who might benefit from imatinib to those with somatic exon 8 KIT mutations. Such mutations should be looked for in patients with mucosal melanoma.
authors.affiliation: aDivision of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center bMelanoma Disease Group, Medstar-Georgetown Cancer Network, Washington, District of Columbia cDivision of Surgical Oncology, Medstar-Georgetown University Hospital, USA.
authors.forename: Suthee
authors.initials: S
authors.lastname: Rapisuwon
authors.forename: Kellie
authors.initials: K
authors.lastname: Parks
authors.forename: Waddah
authors.initials: W
authors.lastname: Al-Refaie
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use*; D001706:Biopsy; D004252:DNA Mutational Analysis; D005091:Exons; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics*; D008875:Middle Aged; D009092:Mucous Membrane / Q000473:pathology; D009154:Mutation; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019089:Stem Cell Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit