NF1-mutated melanomas reveal distinct clinical characteristics depending on tumour origin and respond favourably to immune checkpoint inhibitors

Carl M. Thielmann, Eleftheria Chorti, Johanna Matull, Rajmohan Murali, Anne Zaremba, Georg Lodde, Philipp Jansen, Luisa Richter, Julia Kretz, Inga Möller, Antje Sucker, Rudolf Herbst, Patrick Terheyden, Jochen Utikal, Claudia Pföhler, Jens Ulrich, Alexander Kreuter, Peter Mohr, Ralf Gutzmer, Friedegund MeierEdgar Dippel, Michael Weichenthal, Annette Paschen, Elisabeth Livingstone, Lisa Zimmer, Dirk Schadendorf, Eva Hadaschik, Selma Ugurel, Klaus G. Griewank*

*Corresponding author for this work
11 Citations (Scopus)


Background: NF1-mutated tumours represent a small subset (10–15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1-mutated melanomas to date. Methods: This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1-mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432). Results: Most NF1-mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1-mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF, RAS and triple wild-type melanomas. NF1-mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1-mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1-mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1-mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively). Conclusions: Cutaneous, acral and mucosal NF1-mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy.

Original languageEnglish
JournalEuropean Journal of Cancer
Pages (from-to)113-124
Number of pages12
Publication statusPublished - 12.2021

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)
  • Research Area: Luebeck Integrated Oncology Network (LION)
  • Centers: University Cancer Center Schleswig-Holstein (UCCSH)

DFG Research Classification Scheme

  • 205-14 Haematology, Oncology
  • 205-19 Dermatology
  • 204-05 Immunology

Cite this