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NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics.

ABSTRACT: In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

SUBMITTER: Cirenajwis H

PROVIDER: S-EPMC5527484 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics.

Cirenajwis Helena H Lauss Martin M Ekedahl Henrik H Törngren Therese T Kvist Anders A Saal Lao H LH Olsson Håkan H Staaf Johan J Carneiro Ana A Ingvar Christian C Harbst Katja K Hayward Nicholas K NK Jönsson Göran G

Molecular oncology 20170324 4

In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation d ...[more]

PMID: 28267273

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Project description: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.

Dataset Information

NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics.

Publications

NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics.

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