title: Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis.
abstract: 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.
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Jahn
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kashofer
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Halbwedl
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Winter
authors.affiliation: Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
authors.forename: Laila
authors.initials: L
authors.lastname: El-Shabrawi-Caelen
authors.affiliation: Dermatopathologie Bodensee, Friedrichshafen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mentzel
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl-Atzwanger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D000096142:Cutaneous Malignant Melanoma
chemical_list: D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D048493:Proto-Oncogene Proteins B-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; C508053:ERBB2 protein, human; C579846:NRAS protein, human