Zaremba Anne, Jansen Philipp, Murali Rajmohan, Mayakonda Anand, Riedel Anna, Krahl Dieter, Burkhardt Hans, John Stefan, Géraud Cyrill, Philip Manuel, Kretz Julia, Möller Inga, Stadtler Nadine, Sucker Antje, Paschen Annette, Ugurel Selma, Zimmer Lisa, Livingstone Elisabeth, Horn Susanne, Plass Christoph, Schadendorf Dirk, Hadaschik Eva, Lutsik Pavlo, Griewank Klaus
Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
Cancers (Basel). 2022 Aug 23;14(17):4066. doi: 10.3390/cancers14174066.
Melanocytic neoplasms have been genetically characterized in detail during the last decade. Recurrent exon 3 mutations have been recognized in the distinct group of melanocytic tumors showing deep penetrating nevus-like morphology. In addition, they have been identified in 1-2% of advanced melanoma. Performing a detailed genetic analysis of difficult-to-classify nevi and melanomas with mutations, we found that benign tumors (nevi) show characteristic morphological, genetic and epigenetic traits, which distinguish them from other nevi and melanoma. Malignant -mutant tumors (melanomas) demonstrated a different genetic profile, instead grouping clearly with other non- melanomas in methylation assays. To further evaluate the role of mutations in melanoma, we assessed a large cohort of clinically sequenced melanomas, identifying 38 tumors with exon 3 mutations, including recurrent S45 ( = 13, 34%), G34 ( = 5, 13%), and S27 ( = 5, 13%) mutations. Locations and histological subtype of -mutated melanoma varied; none were reported as showing deep penetrating nevus-like morphology. The most frequent concurrent activating mutations were V600 ( = 21, 55%) and Q61 ( = 13, 34%). In our cohort, four of seven (58%) and one of nine (11%) patients treated with targeted therapy (BRAF and MEK Inhibitors) or immune-checkpoint therapy, respectively, showed disease control (partial response or stable disease). In summary, mutations are associated with a unique melanocytic tumor type in benign tumors (nevi), which can be applied in a diagnostic setting. In advanced disease, no clear characteristics distinguishing -mutant from other melanomas were observed; however, studies of larger, optimally prospective, cohorts are warranted.
在过去十年中，黑素细胞肿瘤已得到详细的基因特征分析。在表现为深浸润痣样形态的独特黑素细胞肿瘤组中，已识别出复发性外显子3突变。此外，在1%-2%的晚期黑色素瘤中也发现了这些突变。通过对难以分类的痣和有突变的黑色素瘤进行详细的基因分析，我们发现良性肿瘤（痣）表现出特征性的形态、基因和表观遗传特征，这使它们有别于其他痣和黑色素瘤。恶性突变肿瘤（黑色素瘤）表现出不同的基因谱，在甲基化检测中反而与其他非黑色素瘤明显分组。为了进一步评估突变在黑色素瘤中的作用，我们评估了一大组经临床测序的黑色素瘤，鉴定出38例具有外显子3突变的肿瘤，包括复发性S45（n = 13，34%）、G34（n = 5，13%）和S27（n = 5，13%）突变。突变型黑色素瘤的位置和组织学亚型各不相同；没有报告显示有深浸润痣样形态。最常见的同时发生的激活突变是V600（n = 21，55%）和Q61（n = 13，34%）。在我们的队列中，接受靶向治疗（BRAF和MEK抑制剂）或免疫检查点治疗的患者中，分别有七分之四（58%）和九分之一（11%）表现出疾病控制（部分缓解或疾病稳定）。总之，突变与良性肿瘤（痣）中一种独特的黑素细胞肿瘤类型相关，可应用于诊断。在晚期疾病中，未观察到区分突变型与其他黑色素瘤的明确特征；然而，有必要对更大规模、最佳前瞻性队列进行研究。
