title: The Genetic Evolution of Melanoma from Precursor Lesions.
abstract: BACKGROUND
  The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known.
  
  
  METHODS
  We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas.
  
  
  RESULTS
  Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed.
  
  
  CONCLUSIONS
  Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.).
authors.affiliation: From the Departments of Dermatology and Pathology (A.H.S., I.Y., E.T., A.G., J.N., L.P., B.R., B.C.B.) and the Helen Diller Family Comprehensive Cancer Center (A.H.S., I.Y., E.T., A.G., B.C.B.), University of California, San Francisco (UCSF), San Francisco; the Departments of Dermatology and Pathology, Cleveland Clinic, Cleveland (I.K.); the Department of Pathology, Orlando Health, Orlando, FL (A.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); and the Department of Dermatology, Dorset County Hospital, Dorchester (C.D.), and the Department of Dermatology, St. John's Institute of Dermatology, London (W.R., A.R.) - both in the United Kingdom.
authors.forename: A Hunter
authors.initials: AH
authors.lastname: Shain
authors.forename: Iwei
authors.initials: I
authors.lastname: Yeh
authors.forename: Ivanka
authors.initials: I
authors.lastname: Kovalyshyn
authors.forename: Aravindhan
authors.initials: A
authors.lastname: Sriharan
authors.forename: Eric
authors.initials: E
authors.lastname: Talevich
authors.forename: Alexander
authors.initials: A
authors.lastname: Gagnon
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Jeffrey
authors.initials: J
authors.lastname: North
authors.forename: Laura
authors.initials: L
authors.lastname: Pincus
authors.forename: Beth
authors.initials: B
authors.lastname: Ruben
authors.forename: William
authors.initials: W
authors.lastname: Rickaby
authors.forename: Corrado
authors.initials: C
authors.lastname: D'Arrigo
authors.forename: Alistair
authors.initials: A
authors.lastname: Robson
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D056915:DNA Copy Number Variations; D018450:Disease Progression; D019143:Evolution, Molecular; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009508:Nevus, Pigmented / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*