Abstract
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.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Most melanomas harbor driver mutations which promote activation of the MAP Kinase pathway, most frequently through mutations in BRAF, NRAS, or NF1 [1,2,3,4].Increasingly, gene fusions involving various kinases, including ALK, ROS1, BRAF, RAF1, NTRK1, and NTRK3 have been identified within melanomas, and these fusion-positive melanomas often display spitzoid morphology [5,6,7,8,9]
Prompted by recent studies of mutual exclusivity among BRAF mutation and MAP2K1 mutation in Langerhans cell histiocytosis (LCH) [13,14,15], as well as work showing distinct functional classes of MAP2K1 mutations [16], we probed a database of clinical specimens with comprehensive genomic profiles for the relationship between MAP2K1 mutations and other driver mutations in melanoma
While previously reported single nucleotide variant (SNV) of MAP2K1 in melanoma have been characterized as secondary oncogenic drivers typically paired with common driver mutations of the MAP kinase (MAPK) pathway, MAP2K1 deletions, as described here, delineate a unique subset of triple wild-type melanoma (2.0% of all triple wild-type melanoma in this cohort)
Summary
Gene fusions involving various kinases, including ALK, ROS1, BRAF, RAF1, NTRK1, and NTRK3 have been identified within melanomas, and these fusion-positive melanomas often display spitzoid morphology [5,6,7,8,9]. In addition to these primary driver mutations, various secondary oncogenic driver mutations have been identified, including gain of function alterations, such as TERT promoter mutation and CDK4 amplification, and loss of function alterations, such as CDKN2A, TP53, and PTEN mutations [2]. We report a series of melanomas with MAP2K1 in-frame deletions distinct from other driver mutations of melanoma
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