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


Authors: Thielmann, C. M.; Chorti, E.; Matull, J.; Murali, R.; Zaremba, A.; Lodde, G.; Jansen, P.; Richter, L.; Kretz, J.; Möller, I.; Sucker, A.; Herbst, R.; Terheyden, P.; Utikal, J.; Pföhler, C.; Ulrich, J.; Kreuter, A.; Mohr, P.; Gutzmer, R.; Meier, F.; Dippel, E.; Weichenthal, M.; Paschen, A.; Livingstone, E.; Zimmer, L.; Schadendorf, D.; Hadaschik, E.; Ugurel, S.; Griewank, K. G.
Article Title: NF1-mutated melanomas reveal distinct clinical characteristics depending on tumour origin and respond favourably to immune checkpoint inhibitors
Abstract: 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. © 2021 Elsevier Ltd
Keywords: adolescent; adult; cancer survival; treatment response; aged; gene mutation; major clinical study; overall survival; promoter region; cancer patient; prospective study; ipilimumab; melanoma; cohort analysis; wild type; mutator gene; multicenter study; telomerase reverse transcriptase; cancer registry; ras protein; cancer tissue; tumor gene; b raf kinase; braf; cutaneous melanoma; nf1; mucosal melanoma; nras; nf1 gene; immune checkpoint inhibitor; high throughput sequencing; acral melanoma; nivolumab; human; male; female; article; pembrolizumab; mutation profiling
Journal Title: European Journal of Cancer
Volume: 159
ISSN: 0959-8049
Publisher: Elsevier Inc.  
Date Published: 2021-12-01
Start Page: 113
End Page: 124
Language: English
DOI: 10.1016/j.ejca.2021.09.035
PROVIDER: scopus
PUBMED: 34742158
PMCID: PMC9431958
DOI/URL:
Notes: Article -- Export Date: 1 December 2021 -- Source: Scopus
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  1. Rajmohan Murali
    220 Murali