Abstract

MET exon 14 skipping mutations lead to persistent and upregulated receptor activity which drives cancer. Two new MET-tyrosine kinase inhibitors, capmatinib and tepotinib, were recently FDA-approved for non-small cell lung cancers harboring this mutation. To the authors’ knowledge, this mutation has not been previously reported in melanoma, aside from one case in a large cohort series of solid tumors that included melanomas. However the clinical and pathological characteristics of melanoma harboring this mutation remain unknown. Herein we report a case of malignant melanoma with a MET exon 14 skipping mutation. A male in his 70s with a history of recurrent desmoplastic/spindle cell melanoma of the scalp initially diagnosed 4 years prior, presented with a new, one centimeter subcutaneous nodule on his adjacent scalp. Biopsy revealed a spindled neoplasm positive for melanocytic markers with surrounding tertiary lymphoid structures, consistent with spindle cell melanoma. Next generation DNA sequencing revealed multiple mutations, most notably MET splice site p.D1028N mutation. RNA sequencing revealed MET mRNA transcript with exon 14 skipping due to fusion involving exon 13 and exon 15. The specimen harbored additional mutations in RAC1 and TERT promoter region but lacked mutations in other common melanoma-related genes. At the time of this report, the patient currently has no evidence of distant spread based on imaging studies and is undergoing radiation therapy after resection with negative margins. This novel mutational discovery of MET exon 14 skipping in a case of melanoma holds promise for potentially advancing targetable melanoma therapies. This melanoma, with spindle cell morphology and tertiary lymphoid structures, predicts a relatively better prognostic course by histology. However, due to the rarity of this alteration in melanoma, the phenotypic characteristics and therapeutic significance are currently unknown, but warrant additional investigation.

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