Characterisation and outcome of RAC1 mutated melanoma

Eur J Cancer. 2023 Apr:183:1-10. doi: 10.1016/j.ejca.2023.01.009. Epub 2023 Jan 18.


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.

Keywords: Immune checkpoint inhibition; Melanoma; Mutational analysis; RAC1 mutation; Systemic treatment; Targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Melanoma* / drug therapy
  • Mutation
  • Prospective Studies
  • Proto-Oncogene Proteins B-raf / genetics
  • Retrospective Studies
  • Skin Neoplasms* / pathology
  • rac1 GTP-Binding Protein / genetics


  • Proto-Oncogene Proteins B-raf
  • RAC1 protein, human
  • rac1 GTP-Binding Protein