Novel somatic KIT exon 8 mutation with dramatic response to imatinib in a patient with mucosal melanoma

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.

Localized sinonasal mucosal melanoma: Outcomes and associations with stage, radiotherapy, and positron emission tomography response

“…While mutational status did not confer prognostic value in our study, perhaps the value of mutational analysis likely resides in future attempts at therapy targeted at these pathways. 27 …”

“…Although mutational status did not confer prognostic value in our study, perhaps the value of mutational analysis likely resides in future attempts at therapy targeted at these pathways. 27 The role of RT has remained controversial for sinonasal mucosal melanoma. Eighty-two percent of patients (64/ 78) with localized sinonasal mucosal melanoma at MSKCC received adjuvant or definitive RT after surgery, consistent with common practice based on retrospective series.…”

RTK Inhibitors in Melanoma: From Bench to Bedside

“…Particularly, it was reported that melanoma non-responders harbor specific c-KIT mutations known to confer imatinib resistance in GIST, such as D820Y, N822K, and A829P, while responders show mutation on exon 11 or exon 13 [31,32]. In 2014, a case report expanded the melanoma population that could benefit from imatinib to those with somatic exon 8 KIT mutations [46].…”

Development and validation of a nomogram for predicting overall survival in patients with sinonasal mucosal melanoma

“…Similar results were achieved by Amit et al and Chraybi et al [ 26 , 27 ], who reported that these mutations could be used for direct targeted therapy. Targeted therapy has provided promising results in the treatment of SNMM [ 23 , 28 ]. Cao et al recently reported that an SNMM patient with a ROS1 fusion achieved complete remission after 8 months of treatment with crizotinib [ 29 ].…”