Desmoplastic
malignant melanoma is a distinct
melanoma entity histologically subtyped into mixed and pure forms due to significantly reduced
lymph node metastases in the pure form. Recent reports investigating common actionable driver mutations have demonstrated a lack of BRAF, NRAS, and KIT mutation in pure desmoplastic
melanoma. In search for alternative driver mutations next generation amplicon sequencing for hotspot mutations in 50 genes cardinal to
tumorigenesis was performed and in addition the RET G691S polymorphism was investigated. Data from 21 desmoplastic
melanomas (12 pure and 9 mixed) were retrieved. Pure desmoplastic
melanomas were either devoid of mutations (50%) or displayed mutations in tumor suppressor genes (TP53, CDKN2A, and SMAD4) singularly or in combination with the exception of a PIK3CA double-mutation lacking established biological relevance. Mixed desmoplastic
melanomas on the contrary were frequently mutated (89%), and 67% exhibited activating mutations similar to common-type
cutaneous malignant melanomas (BRAF, NRAS, FGFR2, and ERBB2). Separate analysis of morphologically heterogeneous
tumor areas in four mixed desmoplastic
malignant melanomas displayed no difference in mutation status and RET G691 status. GNAQ and GNA11, two oncogenes in BRAF and NRAS wild-type uveal
melanomas, were not mutated in our cohort. The RET G691S polymorphism was found in 25% of pure and 38% of mixed desmoplastic
melanomas. Apart from RET G691S our findings demonstrate absence of activating driver mutations in pure desmoplastic
melanoma beyond previously investigated oncogenes (BRAF, NRAS, and KIT). The findings underline the therapeutic dichotomy of mixed versus pure desmoplastic
melanoma with regard to activating mutations primarily of the
mitogen-activated protein kinase pathway.