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
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, 72076 Tübingen, Germany.
Derpartment of Dermatology, Venerology and Allergology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Cancers (Basel). 2020 Aug 20;12(9):2359. doi: 10.3390/cancers12092359.
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 and , we frequently observed deletions. Acral and mucosal melanomas were dominated by CNV alterations affecting , , , , and . Uveal melanoma often had somatic SNVs in and amplification of in all cases. A significantly higher incidence of V600 mutations and amplifications, and 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.
通过下一代测序（NGS）检测体细胞驱动突变在晚期黑色素瘤患者的治疗中变得越来越重要。在我们的研究中，我们评估了2017年来自临床常规的82例黑色素瘤患者的NGS结果。除了确定肿瘤突变负荷（TMB）和注释所有基因驱动改变外，我们还研究了它们作为免疫检查点抑制剂（ICI）耐药预测指标的潜力以及作为黑色素瘤亚型之间的鉴别特征。原发灶不明的黑色素瘤与皮肤黑色素瘤具有相似的突变模式和TMB，这提示其皮肤起源。除了BRAF和NRAS中的典型热点突变外，我们还经常观察到CDKN2A缺失。肢端和黏膜黑色素瘤主要由影响TERT、TP53、RB1、PTEN、CDKN2A和NF1的拷贝数变异（CNV）改变所主导。葡萄膜黑色素瘤在所有病例中通常在GNAQ和GNA11中有体细胞单核苷酸变异（SNV）以及BAP1扩增。在接受ICI治疗时疾病进展的患者中发现BRAF V600突变、NRAS扩增、CDKN2A和PTEN缺失的发生率显著更高。因此，NGS可能有助于更精确地表征黑色素瘤亚型并确定ICI治疗可能的耐药机制。然而，需要包括更大队列的基于NGS的研究来支持潜在的遗传性ICI耐药机制。
