title: A primary melanoma and its asynchronous metastasis highlight the role of BRAF, CDKN2A, and TERT.
abstract: BACKGROUND
  Alterations in pathways including BRAF, CDKN2A, and TERT contribute to the development of melanoma, but the sequence in which the genetic alterations occur and their prognostic significance remains unclear. To clarify the role of these pathways, we analyzed a primary melanoma and its metastasis.
  
  
  METHODS
  Immunohistochemistry for BRAF-V600E, Sanger sequencing of BRAF and the TERT promoter, fluorescence in-situ hybridization, and telomere analyses were performed on a primary melanoma and its asynchronous cerebellar metastasis. Using the log-rank test and Cox-proportional model, the cancer genome atlas (TCGA) cohort of melanomas was analyzed for the effect of BRAF mutation and CDKN2A loss on survival.
  
  
  RESULTS
  The primary melanoma expressed mutant BRAF-V600E and possessed a homozygous deletion of CDKN2A. In addition to these early defects, the metastatic lesion also possessed evidence of aneuploidy and an activating mutation of the TERT promoter. In the TCGA melanoma cohort, there was a non-significant trend toward poor prognosis in early stage cutaneous melanoma patients with concomitant BRAF mutation and CDKN2A loss.
  
  
  CONCLUSIONS
  BRAF mutation and CDKN2A loss occurred early and TERT promoter mutation later in a case of lethal metastatic melanoma. The effects of these pathways on survival warrant further investigation in early stage cutaneous melanoma patients.
authors.affiliation: Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA; ProPath, Dallas, TX, USA; Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hosler
authors.forename: Teresa
authors.initials: T
authors.lastname: Davoli
authors.forename: Ilgen
authors.initials: I
authors.lastname: Mender
authors.forename: Brandon
authors.initials: B
authors.lastname: Litzner
authors.forename: Jaehyuk
authors.initials: J
authors.lastname: Choi
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wang
mesh_terms: D000328:Adult; D001483:Base Sequence; D005260:Female; D005500:Follow-Up Studies; D019942:Genes, p16; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000556:secondary*; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms; D019098:Telomerase / Q000235:genetics*; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase
keywords: BRAF; CDKN2A; FISH; TERT; melanoma