Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients

The detection of somatic driver mutations by next-generation sequencing (NGS) is becoming increasingly important in the care of advanced melanoma patients. In our study, we evaluated the NGS results of 82 melanoma patients from clinical routine in 2017. Besides determining the tumor mutational burde...

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Bibliographic Details
Published in:Cancers 2020-09, Vol.12 (9), p.2359
Main Authors: Hilke, Franz J., Sinnberg, Tobias, Gschwind, Axel, Niessner, Heike, Demidov, German, Amaral, Teresa, Ossowski, Stephan, Bonzheim, Irina, Röcken, Martin, Riess, Olaf, Garbe, Claus, Schroeder, Christopher, Forschner, Andrea
Format: Article
Language:English
Subjects:
Cell cycle
Cyclin-dependent kinase 4
Epidermal growth factor receptors
Gene mutation
Genes
Genetic aspects
Genomes
Health aspects
Immune checkpoint inhibitors
Immunotherapy
Kinases
Melanoma
Metastasis
Mucosa
Mutation
Mutation hot spots
Myc protein
Next-generation sequencing
p53 Protein
Patients
PTEN protein
Software
Tumors
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Summary:The detection of somatic driver mutations by next-generation sequencing (NGS) is becoming increasingly important in the care of advanced melanoma patients. In our study, we evaluated the NGS results of 82 melanoma patients from clinical routine in 2017. Besides determining the tumor mutational burden (TMB) and annotation of all genetic driver alterations, we investigated their potential as a predictor for resistance to immune checkpoint inhibitors (ICI) and as a distinguishing feature between melanoma subtypes. Melanomas of unknown primary had a similar mutation pattern and TMB to cutaneous melanoma, which hints at its cutaneous origin. Besides the typical hotspot mutation in BRAF and NRAS, we frequently observed CDKN2A deletions. Acral and mucosal melanomas were dominated by CNV alterations affecting PDGFRA, KIT, CDK4, RICTOR, CCND2 and CHEK2. Uveal melanoma often had somatic SNVs in GNA11/Q and amplification of MYC in all cases. A significantly higher incidence of BRAF V600 mutations and EGFR amplifications, PTEN and TP53 deletions was found in patients with disease progression while on ICI. Thus, NGS might help to characterize melanoma subtypes more precisely and to identify possible resistance mechanisms to ICI therapy. Nevertheless, NGS based studies, including larger cohorts, are needed to support potential genetic ICI resistance mechanisms.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12092359