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@ARTICLE{Lodde:267548,
      author       = {G. C. Lodde and P. Jansen and R. Herbst and P. Terheyden
                      and J. Utikal$^*$ and C. Pföhler and J. Ulrich and A.
                      Kreuter and P. Mohr and R. Gutzmer and F. Meier$^*$ and E.
                      Dippel and M. Weichenthal and A. Sucker and J.-M. Placke and
                      A. Zaremba and L. J. Albrecht and B. Kowall and W. Galetzka
                      and J. C. Becker$^*$ and A. Tasdogan and L. Zimmer and E.
                      Livingstone and E. Hadaschik and D. Schadendorf$^*$ and S.
                      Ugurel$^*$ and K. Griewank},
      title        = {{C}haracterisation and outcome of {RAC}1 mutated melanoma.},
      journal      = {European journal of cancer},
      volume       = {183},
      issn         = {0014-2964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-00326},
      pages        = {1 - 10},
      year         = {2023},
      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.},
      keywords     = {Immune checkpoint inhibition (Other) / Melanoma (Other) /
                      Mutational analysis (Other) / RAC1 mutation (Other) /
                      Systemic treatment (Other) / Targeted therapy (Other)},
      cin          = {A370 / HD01 / DD01 / ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)A370-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)DD01-20160331 / I:(DE-He78)ED01-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36773463},
      doi          = {10.1016/j.ejca.2023.01.009},
      url          = {https://inrepo02.dkfz.de/record/267548},
}