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Open AccessArticle

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

1
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, 72076 Tübingen, Germany
2
Derpartment of Dermatology, Venerology and Allergology, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany
3
Image-Guided and Functionally Instructed Tumor Therapies (iFIT) Cluster of Excellence (EXC 2180), University of Tübingen, 72076 Tübingen, Germany
4
Department of Dermatology, University Hospital Tübingen, 72076 Tübingen, Germany
5
Portuguese Air Force Health Care Direction, 1649-020 Lisbon, Portugal
6
German DFG NGS Competence Center, NCCT, 72076 Tübingen, Germany
7
Institute of Pathology and Neuropathology, University Hospital Tübingen, 72076 Tübingen, Germany
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2359; https://doi.org/10.3390/cancers12092359
Received: 28 July 2020 / Revised: 14 August 2020 / Accepted: 16 August 2020 / Published: 20 August 2020
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. View Full-Text
Keywords: Genome of advanced melanoma; acral; mucosal; uveal; melanoma of unknown origin; tumor mutation burden; TMB; immune checkpoint inhibitors; next-generation sequencing Genome of advanced melanoma; acral; mucosal; uveal; melanoma of unknown origin; tumor mutation burden; TMB; immune checkpoint inhibitors; next-generation sequencing
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Hilke, F.J.; Sinnberg, T.; Gschwind, A.; Niessner, H.; Demidov, G.; Amaral, T.; Ossowski, S.; Bonzheim, I.; Röcken, M.; Riess, O.; Garbe, C.; Schroeder, C.; Forschner, A. Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients. Cancers 2020, 12, 2359.

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