Single-center clinico-genomic analysis of KIT mutated melanomas and clinical outcomes with tyrosine kinase inhibitor treatment

Thielmann, Carl Maximilian; Livingstone, Elisabeth; Kretz, Julia; Krefting, Frederik; Jansen, Philipp; Möller, Inga; Rambow, Florian; Seier, Johanna Andrea; Lodde, Georg; Tapken, Henry Karl; Forschner, Andrea; Schielke, Lisa; Paschen, Annette; Albrecht, Lea Jessica; Sucker, Antje; Hadaschik, Eva; Tasdogan, Alpaslan; Sternberg, Jan; Ocker-Serger, Lennart; Zaremba, Anne; Placke, Jan-Malte; Richter, Luisa; Schadendorf, Dirk; Griewank, Klaus; Bauer, Sebastian; Zimmer, Lisa

doi:10.1016/j.ejcskn.2026.101152

Journal Article

DKFZ-2026-01750

Single-center clinico-genomic analysis of KIT mutated melanomas and clinical outcomes with tyrosine kinase inhibitor treatment

Thielmann, C. M.DKFZ* ; Richter, L.DKFZ* ; Tapken, H. K.DKFZ* ; Seier, J. A.DKFZ* ; Schielke, L.DKFZ* ; Sternberg, J.DKFZ* ; Kretz, J.DKFZ* ; Möller, I.DKFZ* ; Sucker, A.DKFZ* ; Paschen, A.DKFZ* ; Ocker-Serger, L.DKFZ* ; Krefting, F.DKFZ* ; Zaremba, A.DKFZ* ; Albrecht, L. J.DKFZ* ; Zimmer, L.DKFZ* ; Livingstone, E.DKFZ* ; Lodde, G.DKFZ* ; Tasdogan, A.DKFZ* ; Placke, J.-M.DKFZ* ; Hadaschik, E.DKFZ* ; Rambow, F. ; Bauer, S. ; Forschner, A. ; Schadendorf, D.DKFZ* ; Jansen, P.DKFZ* ; Griewank, K.DKFZ*

2026
Elsevier B.V. Amsterdam

EJC skin cancer 4, 101152 (2026) [10.1016/j.ejcskn.2026.101152]

Abstract: Background: KIT alterations occur in distinct melanoma subtypes, yet KIT-mutant melanoma remains clinically and biologically heterogeneous and lacks approved KIT-targeted therapy. We characterized clinico-genomic features of KIT-altered melanoma and described outcomes of patients treated with tyrosine kinase inhibitors (TKI). Methods: In this retrospective cohort study, we reviewed 3837 next-generation sequencing (NGS) reports from the Department of Dermatology, University Hospital Essen (2013–2024) and identified 97 patients with KIT-mutated melanoma. Tumors were classified as KIT hotspot (activating, recurrent variants; n = 18) or non-hotspot (n = 79). Clinical characteristics, mutational landscape, number of detected mutations, UV-associated substitution patterns, and survival outcomes were analyzed; five KIT-mutant patients treated with TKIs were described in detail. Results: Most cases were of cutaneous (82/97) origin, while other subgroups included mucosal (7/97) and melanoma of unknown primary (8/97). KIT hotspot mutations were enriched in acral and mucosal primaries and were mutually exclusive with BRAF V600 and NRAS Q61/G12 mutations, whereas non-hotspot tumors frequently harbored canonical drivers (BRAF V600 22.8%, NRAS Q61/G12 17.7%). NF1 mutations were markedly enriched in non-hotspot tumors (62.0% vs 16.7%; p < 0.001). In cutaneous melanoma, non-hotspot mutant tumors showed higher number of mutations than hotspot mutant tumors (median 13 vs 3; p < 0.001) and a more pronounced UV mutation signature. Five patients received TKIs (imatinib, ripretinib, sunitinib, nilotinib) with responses ranging from mixed to complete responses. Conclusions: KIT hotspot and non-hotspot variants define biologically distinct subsets of KIT-altered melanoma. Non-hotspot KIT variants frequently co-occur with NF1-mutations and high-mutation numbers, supporting a passenger role in many cases, whereas hotspot KIT marks a targetable dependency and warrants repeat profiling at progression.

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