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

被引:42
作者
Hilke, Franz J. [1 ,2 ]
Sinnberg, Tobias [3 ]
Gschwind, Axel [1 ]
Niessner, Heike [4 ]
Demidov, German [1 ]
Amaral, Teresa [4 ,5 ]
Ossowski, Stephan [1 ,6 ]
Bonzheim, Irina [7 ]
Roecken, Martin [4 ]
Riess, Olaf [1 ,6 ]
Garbe, Claus [4 ]
Schroeder, Christopher [1 ]
Forschner, Andrea [4 ]
机构
[1] Univ Hosp Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany
[2] Charite Univ Med Berlin, Derpartment Dermatol Venerol & Allergol, D-10117 Berlin, Germany
[3] Univ Tubingen, Image Guided & Functionally Instructed Tumor Ther, D-72076 Tubingen, Germany
[4] Univ Hosp Tubingen, Dept Dermatol, D-72076 Tubingen, Germany
[5] Portuguese Air Force Hlth Care Direct, P-1649020 Lisbon, Portugal
[6] NCCT, German DFG NGS Competence Ctr, D-72076 Tubingen, Germany
[7] Univ Hosp Tubingen, Inst Pathol & Neuropathol, D-72076 Tubingen, Germany
关键词
Genome of advanced melanoma; acral; mucosal; uveal; melanoma of unknown origin; tumor mutation burden; TMB; immune checkpoint inhibitors; next-generation sequencing; CHECKPOINT INHIBITORS; CLINICAL-RESPONSE; CTLA-4; BLOCKADE; MYC; HYPERPROGRESSORS; HETEROGENEITY; ABERRATIONS; RESISTANCE; SURVIVAL; PATHWAY;
D O I
10.3390/cancers12092359
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
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页码:1 / 15
页数:15
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