title: Immunohistochemical analysis of molecular drivers in melanoma identifies p16 as an independent prognostic biomarker.
abstract: OBJECTIVE
  To perform immunohistochemical (IHC) analysis of molecular drivers related to the development and maintenance of melanoma and to assess their value as diagnostic and prognostic melanoma biomarkers in routine clinical practice.
  
  
  METHODS
  Tissue microarrays constructed from a cohort of primary melanomas (n=355), benign naevi (n=37) and melanoma metastases (n=14) were evaluated for IHC expression of c-KIT, BRAF(V600E), MITF, p16, p53 and PTEN, as well as for pERK, a surrogate marker for mitogen-activated protein kinase pathway activation. The results were correlated with clinicopathological parameters and clinical outcome.
  
  
  RESULTS
  Absent p16 expression and reduced MITF expression were both associated with the adverse prognostic markers ulceration (p=0.009 and p<0.0001, respectively), advanced tumour stage (p<0.0001 and p=0.001, respectively) and higher Breslow thickness (both p<0.0001), as well as with an adverse overall relapse-free survival (p<0.0001 and p=0.003, respectively). Absence of p16 expression predicted overall relapse-free (p=0.02) and distant metastasis-free (p=0.04) survival, independently of Breslow thickness, ulceration and tumour stage.
  
  
  CONCLUSIONS
  IHC determined p16 expression is an independent prognostic biomarker of potential value in routine melanoma diagnostic practice.
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Johanne
authors.initials: J
authors.lastname: Lade-Keller
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Riber-Hansen
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.affiliation: Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Stephen Jacques
authors.initials: SJ
authors.lastname: Hamilton-Dutoit
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Steiniche
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000737:chemistry* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D051739:Microphthalmia-Associated Transcription Factor / Q000032:analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D012878:Skin Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor
keywords: Cancer Research; Immunohistochemistry; Melanoma; Oncogenes; Skin Tumours