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

• Main Authors: Franz J. Hilke, Tobias Sinnberg, Axel Gschwind, Heike Niessner, German Demidov, Teresa Amaral, Stephan Ossowski, Irina Bonzheim, Martin Röcken, Olaf Riess, Claus Garbe, Christopher Schroeder, Andrea Forschner
• Format: Article
• Language: English
• Published: MDPI AG 2020-08-01
• Series: Cancers
• Subjects: Genome of advanced melanoma; acral; mucosal; uveal; melanoma of unknown origin; tumor mutation burden
• Online Access: https://www.mdpi.com/2072-6694/12/9/2359

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 <i>BRAF</i> and <i>NRAS</i>, we frequently observed <i>CDKN2A</i> deletions. Acral and mucosal melanomas were dominated by CNV alterations affecting <i>PDGFRA</i>, <i>KIT</i>, <i>CDK4</i>, <i>RICTOR</i>, <i>CCND2</i> and <i>CHEK2</i>. Uveal melanoma often had somatic SNVs in <i>GNA11/Q</i> and amplification of <i>MYC</i> in all cases. A significantly higher incidence of <i>BRAF</i> V600 mutations and <i>EGFR</i> amplifications, <i>PTEN</i> and <i>TP53</i> 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.