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Characterisation and outcome of RAC1 mutated melanoma

Background - Activating hot spot R29S mutations in RAC1, a small GTPase influencing several cellular processes including cell proliferation and cytoskeleton rearrangement, have been reported in up to 9% of sun-exposed melanomas. Clinical characteristics and treatment implications of RAC1 mutations i...

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Hauptverfasser: Lodde, Georg Christian (VerfasserIn) , Jansen, Philipp (VerfasserIn) , Herbst, Rudolf (VerfasserIn) , Terheyden, Patrick (VerfasserIn) , Utikal, Jochen (VerfasserIn) , Pföhler, Claudia (VerfasserIn) , Ulrich, Jens (VerfasserIn) , Kreuter, Alexander (VerfasserIn) , Mohr, Peter (VerfasserIn) , Gutzmer, Ralf (VerfasserIn) , Meier, Friedegund (VerfasserIn) , Dippel, Edgar (VerfasserIn) , Weichenthal, Michael (VerfasserIn) , Sucker, Antje (VerfasserIn) , Placke, Jan-Malte (VerfasserIn) , Zaremba, Anne (VerfasserIn) , Albrecht, Lea Jessica (VerfasserIn) , Kowall, Bernd (VerfasserIn) , Galetzka, Wolfgang Johannes (VerfasserIn) , Becker, Jürgen C. (VerfasserIn) , Tasdogan, Alpaslan (VerfasserIn) , Zimmer, Lisa (VerfasserIn) , Livingstone, Elisabeth (VerfasserIn) , Hadaschik, Eva (VerfasserIn) , Schadendorf, Dirk (VerfasserIn) , Ugurel, Selma (VerfasserIn) , Griewank, Klaus (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: April 2023
In: European journal of cancer
Year: 2023, Jahrgang: 183, Pages: 1-10
ISSN:1879-0852
DOI:10.1016/j.ejca.2023.01.009
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ejca.2023.01.009
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0959804923000175
Volltext
Verfasserangaben:Georg C. Lodde, Philipp Jansen, Rudolf Herbst, Patrick Terheyden, Jochen Utikal, Claudia Pföhler, Jens Ulrich, Alexander Kreuter, Peter Mohr, Ralf Gutzmer, Friedegund Meier, Edgar Dippel, Michael Weichenthal, Antje Sucker, Jan-Malte Placke, Anne Zaremba, Lea Jessica Albrecht, Bernd Kowall, Wolfgang Galetzka, Jürgen C. Becker, Alpaslan Tasdogan, Lisa Zimmer, Elisabeth Livingstone, Eva Hadaschik, Dirk Schadendorf, Selma Ugurel, Klaus Griewank
Beschreibung
Zusammenfassung:Background - Activating hot spot R29S mutations in RAC1, a small GTPase influencing several cellular processes including cell proliferation and cytoskeleton rearrangement, have been reported in up to 9% of sun-exposed melanomas. Clinical characteristics and treatment implications of RAC1 mutations in melanoma remain unclear. - Methods - We investigated the largest set (n = 64) of RAC1 mutated melanoma patients reported to date, including a retrospective single institution cohort (n = 34) from the University Hospital Essen and a prospective multicentre cohort (n = 30) from the translational study Tissue Registry in Melanoma (TRIM; CA209-578), for patient and tumour characteristics as well as therapy outcomes. - Results - From 3037 sequenced melanoma samples screened RAC1 mutations occurred in ∼2% of samples (64/3037). The most common RAC1 mutation was P29S (95%, 61/64). The majority of tumours had co-occuring MAP kinase mutations (88%, 56/64); mostly activating NRAS (47%, 30/64) mutations, followed by activating BRAF (28%, 18/64) and NF1 (25%, 16/64) mutations. RAC1 mutated melanomas were almost exclusively of cutaneous origin (84%, 54/64) or of unknown primary (MUP, 14%, 9/64). C > T alterations were the most frequent mutation type identified demonstrating a UV-signature for RAC1 mutated melanoma. Most patients with unresectable disease (39) received immune checkpoint inhibitors (ICI) (77%, 30/39). Objective response rate of first-line treatment in patients with stage III/IV disease was 21%; median overall survival was 47.8 months. - Conclusions - RAC1 mutated melanomas are rare, mostly of cutaneous origin and frequently harbour concomitant MAP kinase mutations, particularly in NRAS. Patients with advanced disease benefit from systemic treatment with ICI.
Beschreibung:Online verfügbar: 18. Januar 2023, Artikelversion: 9. Februar 2023
Gesehen am 16.08.2023
Beschreibung:Online Resource
ISSN:1879-0852
DOI:10.1016/j.ejca.2023.01.009

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