title: BRAF/NRAS wild-type melanomas have a high mutation load correlating with histologic and molecular signatures of UV damage.
abstract: OBJECTIVE
  The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features.
  
  
  METHODS
  DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF/NRAS mutational status were investigated.
  
  
  RESULTS
  The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin (P=0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS-mutant tumors (27 vs. 5.6 mutations per Mb; P=0.0001). Tandem CC>TT/GG>AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (P=0.0008) and in BRAF/NRAS WT tumors (P=0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1, KIT, and NOTCH1, were spread over various signaling pathways.
  
  
  CONCLUSIONS
  Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients.
authors.affiliation: Molecular Oncology Laboratory, Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Mar
authors.forename: Stephen Q
authors.initials: SQ
authors.lastname: Wong
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Papenfuss
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
authors.forename: Hojabr
authors.initials: H
authors.lastname: Kakavand
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Andreas
authors.initials: A
authors.lastname: Behren
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Cebon
authors.forename: Rory
authors.initials: R
authors.lastname: Wolfe
authors.forename: John W
authors.initials: JW
authors.lastname: Kelly
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004249:DNA Damage / Q000528:radiation effects; D059472:Exome / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000528:radiation effects*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D014466:Ultraviolet Rays
chemical_list: D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human