Foundation Medicine, Inc., 150 Second Street, Cambridge, MA, 02141, USA.
Department of Pathology, State University of New York Upstate Medical University, 766 Irving Avenue, Syracuse, NY, 13210, USA.
Mod Pathol. 2020 Dec;33(12):2397-2406. doi: 10.1038/s41379-020-0581-5. Epub 2020 Jun 1.
While the genomics of BRAF, NRAS, and other key genes influencing MAP kinase (MAPK) activity have been thoroughly characterized in melanoma, mutations in MAP2K1 (MEK1) have received significantly less attention and have consisted almost entirely of missense mutations considered secondary oncogenic drivers of melanoma. Here, we investigated melanomas with in-frame deletions of MAP2K1, alterations characterized as MAPK-activating in recent experimental models. Our case archive of clinical melanoma samples with comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform was searched for MAP2K1 genetic alterations. Clinical data, pathology reports, and histopathology were reviewed for each case. From a cohort of 7119 advanced melanomas, 37 unique cases (0.5%) featured small in-frame deletions in MAP2K1. These included E102_I103del (n = 11 cases), P105_A106del (n = 8), Q58_E62del (n = 6), I103_K104del (n = 5), I99_K104del (n = 3), L98_I103del (n = 3), and E41_F53del (n = 1). All 37 were wild type for BRAF, NRAS, and NF1 genomic alterations ("triple wild-type"), representing 2.0% of triple wild-type melanomas overall (37/1882). Median age was 66 years and 49% were male. The majority arose from primary cutaneous sites (35/37; 95%) and demonstrated a UV signature when available (21/25; 84%). Tumor mutational burden was typical for cutaneous melanoma (median = 9.6 mut/Mb, range 0-35.7), and frequently mutated genes included TERTp (63%), CDKN2A (46%), TP53 (11%), PTEN (8%), APC (8%), and CTNNB1 (5%). Histopathology revealed a spectrum of appearances typical of melanoma. For comparison, we evaluated 221 cases with pathogenic missense single nucleotide variants in MAP2K1. The vast majority of melanomas with missense SNVs in MAP2K1 showed co-mutations in BRAF (58%), NF1 (23%), or NRAS (18%). In-frame deletions in MAP2K1, previously shown in experimental models to be strongly MAPK-activating, characterized a significant subset of triple wild-type melanoma (2.0%), suggesting a primary oncogenic role for these mutations. Comprehensive genomic profiling of melanomas enables detection of this alteration, which may have implications for potential therapeutic options.
虽然 BRAF、NRAS 和其他影响 MAP 激酶 (MAPK) 活性的关键基因的基因组学在黑色素瘤中已得到彻底研究，但 MAP2K1（MEK1）的突变受到的关注要少得多，并且几乎完全由被认为是黑色素瘤次级致癌驱动因素的错义突变组成。在这里，我们研究了具有 MAP2K1 框内缺失的黑色素瘤，这些改变在最近的实验模型中被认为是 MAPK 激活。我们通过基于杂交捕获的 DNA 测序平台对临床黑色素瘤样本进行了综合基因组分析的病例档案，对 MAP2K1 遗传改变进行了搜索。对每个病例的临床数据、病理报告和组织病理学进行了审查。在 7119 例晚期黑色素瘤队列中，37 例具有 MAP2K1 小的框内缺失，包括 E102_I103del（n=11 例）、P105_A106del（n=8 例）、Q58_E62del（n=6 例）、I103_K104del（n=5 例）、I99_K104del（n=3 例）、L98_I103del（n=3 例）和 E41_F53del（n=1 例）。所有 37 例均为 BRAF、NRAS 和 NF1 基因组改变的野生型（“三重野生型”），占总体三重野生型黑色素瘤的 2.0%（37/1882）。中位年龄为 66 岁，49%为男性。大多数源自原发性皮肤部位（37/37；95%），当有 UV 特征时显示 UV 特征（25/25；84%）。肿瘤突变负担与皮肤黑色素瘤典型（中位数=9.6 mut/Mb，范围 0-35.7），经常突变的基因包括 TERTp（63%）、CDKN2A（46%）、TP53（11%）、PTEN（8%）、APC（8%）和 CTNNB1（5%）。组织病理学显示出与黑色素瘤典型的一系列表现。为了比较，我们评估了 221 例 MAP2K1 中具有致病性错义单核苷酸变异的病例。具有 MAP2K1 错义 SNV 的黑色素瘤绝大多数伴有 BRAF（58%）、NF1（23%）或 NRAS（18%）共突变。MAP2K1 中的框内缺失，在实验模型中被证明具有强烈的 MAPK 激活作用，构成了三重野生型黑色素瘤的一个重要亚群（2.0%），表明这些突变具有主要的致癌作用。黑色素瘤的综合基因组分析可检测到这种改变，这可能对潜在的治疗选择有影响。
