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A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma
Franz J Hilke1,2, Tobias Sinnberg3, Axel Gschwind1
1Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, 72076 Tübingen, Germany.
Abstract:
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.
Insights
Next-generation sequencing (NGS) helps characterize melanoma subtypes and predict resistance to immune checkpoint inhibitors (ICI). This study analyzed 82 patients, revealing distinct mutation patterns and potential genetic markers for treatment response.
Area of Science:
- Oncology
- Genomics
- Dermatology
Background:
- Next-generation sequencing (NGS) is crucial for advanced melanoma patient care.
- Understanding genetic alterations aids in treatment strategies and subtype classification.
Purpose of the Study:
- To evaluate NGS results in 82 melanoma patients from clinical routine.
- To determine tumor mutational burden (TMB) and identify genetic driver alterations.
- To investigate the potential of these alterations as predictors of resistance to immune checkpoint inhibitors (ICI) and as distinguishing features between melanoma subtypes.
Main Methods:
- Retrospective analysis of NGS data from 82 melanoma patients.
- Determination of tumor mutational burden (TMB).
- Annotation of genetic driver alterations and copy number variations (CNVs).
Main Results:
- Melanomas of unknown primary showed similar mutation patterns to cutaneous melanoma.
- Acral and mucosal melanomas were characterized by CNV alterations in specific genes (e.g., PDGFRA, KIT).
- Uveal melanoma frequently exhibited SNVs in GNA11/Q and MYC amplification.
- BRAF V600 mutations, EGFR amplifications, and PTEN/TP53 deletions were more common in patients progressing on ICI therapy.
Conclusions:
- NGS can precisely characterize melanoma subtypes and identify potential ICI resistance mechanisms.
- Distinct genetic profiles correlate with melanoma subtypes and treatment response.
- Larger cohort studies are needed to validate genetic markers for ICI resistance.
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