title: 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.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Cirenajwis
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauss
authors.affiliation: Division of Surgery, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekedahl
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Törngren
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Kvist
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Lao H
authors.initials: LH
authors.lastname: Saal
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.|Department of Oncology, Skåne University Hospital, Lund University, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.|Department of Oncology, Skåne University Hospital, Lund University, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Carneiro
authors.affiliation: Division of Surgery, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Harbst
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D015894:Genome, Human; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D025542:Neurofibromin 1
keywords: 
  
  BRAF
  
  ; 
  
  NRAS
  
  ; 
  NF1
  ; melanoma