Journal Article

DKFZ-2023-00326

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Characterisation and outcome of RAC1 mutated melanoma.

Lodde, G. C. ; Jansen, P. ; Herbst, R. ; Terheyden, P. ; Utikal, J.DKFZ* ; Pföhler, C. ; Ulrich, J. ; Kreuter, A. ; Mohr, P. ; Gutzmer, R. ; Meier, F.DKFZ* ; Dippel, E. ; Weichenthal, M. ; Sucker, A. ; Placke, J.-M. ; Zaremba, A. ; Albrecht, L. J. ; Kowall, B. ; Galetzka, W. ; Becker, J. C.DKFZ* ; Tasdogan, A. ; Zimmer, L. ; Livingstone, E. ; Hadaschik, E. ; Schadendorf, D.DKFZ* ; Ugurel, S.DKFZ* ; Griewank, K.

2023
Elsevier Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.ejca.2023.01.009

Abstract: 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.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.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.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.

Keyword(s): Immune checkpoint inhibition ; Melanoma ; Mutational analysis ; RAC1 mutation ; Systemic treatment ; Targeted therapy

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Contributing Institute(s):

1. KKE Dermatoonkologie (A370)
2. DKTK HD zentral (HD01)
3. DKTK DD zentral (DD01)
4. DKTK ED ES zentral (ED01)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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