title: Expression of tumor necrosis factor--related apoptosis-inducing ligand receptors 1 and 2 in melanoma.
abstract: OBJECTIVE
  The proapoptotic receptors tumor necrosis factor--related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and TRAIL-R2 are targets of drugs in clinical development, and receptor expression levels may be important determinants of sensitivity to receptor agonists. We assessed TRAIL-R1 and TRAIL-R2 expression patterns in a large cohort of melanomas and benign nevi.
  
  
  METHODS
  We analyzed tissue microarrays containing 546 melanomas and 540 nevi using our automated quantitative method to measure protein levels in situ (AQUA). The system uses S100 to define pixels as melanoma (tumor mask) within the array spot and measures intensity of TRAIL-receptor expression using Cy5-conjugated antibodies within the mask. AQUA scores were correlated with clinical and pathologic variables.
  
  
  RESULTS
  TRAIL-R1 and TRAIL-R2 expression was higher in melanomas than in nevi (P < 0.0001), and higher in primary than in metastatic specimens (P = 0.0031 and P < 0.0001, respectively). TRAIL-R1 and TRAIL-R2 expression exceeding the 95th percentile for nevi was found in 19% and 74% of melanoma specimens, respectively. Although on univariate analysis, high TRAIL-R2 expression correlated with increased survival (P = 0.0439), it was not associated with survival within the primary or metastatic subcohorts. TRAIL-R1 expression was not associated with survival.
  
  
  CONCLUSIONS
  TRAIL-R1 and TRAIL-R2 expression is higher in malignant melanocytes than in their benign counterparts, suggesting that these receptors might be effective therapeutic targets in melanoma. Expression is higher in early-stage disease than in metastatic specimens, and expression exceeding that found in nevi is found in a substantially larger fraction of melanomas for TRAIL-R2 compared with TRAIL-R1. Assessment of baseline tumor TRAIL receptor expression may be important in analysis of clinical trials involving TRAIL receptor agonists.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Mary M
authors.initials: MM
authors.lastname: McCarthy
authors.forename: Kyle A
authors.initials: KA
authors.lastname: DiVito
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.forename: Daniela
authors.initials: D
authors.lastname: Kovacs
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Berger
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Robert L
authors.initials: RL
authors.lastname: Camp
authors.forename: Rossitza
authors.initials: R
authors.lastname: Lazova
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Harriet M
authors.initials: HM
authors.lastname: Kluger
mesh_terms: D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D012016:Reference Values
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human