title: Whole genome methylation profiles as independent markers of survival in stage IIIC melanoma patients.
abstract: BACKGROUND
  The clinical course of cutaneous melanoma (CM) can differ significantly for patients with identical stages of disease, defined clinico-pathologically, and no molecular markers differentiate patients with such a diverse prognosis. This study aimed to define the prognostic value of whole genome DNA methylation profiles in stage III CM.
  
  
  METHODS
  Genome-wide methylation profiles were evaluated by the Illumina Human Methylation 27 BeadChip assay in short-term neoplastic cell cultures from 45 stage IIIC CM patients. Unsupervised K-means partitioning clustering was exploited to sort patients into 2 groups based on their methylation profiles. Methylation patterns related to the discovered groups were determined using the nearest shrunken centroid classification algorithm. The impact of genome-wide methylation patterns on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analyses.
  
  
  RESULTS
  Unsupervised K-means partitioning by whole genome methylation profiles identified classes with significantly different OS in stage IIIC CM patients. Patients with a "favorable" methylation profile had increased OS (P = 0.001, log-rank = 10.2) by Kaplan-Meier analysis. Median OS of stage IIIC patients with a "favorable" vs. "unfavorable" methylation profile were 31.5 and 10.4 months, respectively. The 5 year OS for stage IIIC patients with a "favorable" methylation profile was 41.2% as compared to 0% for patients with an "unfavorable" methylation profile. Among the variables examined by multivariate Cox regression analysis, classification defined by methylation profile was the only predictor of OS (Hazard Ratio = 2.41, for "unfavorable" methylation profile; 95% Confidence Interval: 1.02-5.70; P = 0.045). A 17 gene methylation signature able to correctly assign prognosis (overall error rate = 0) in stage IIIC patients on the basis of distinct methylation-defined groups was also identified.
  
  
  CONCLUSIONS
  A discrete whole-genome methylation signature has been identified as molecular marker of prognosis for stage IIIC CM patients. Its use in daily practice is foreseeable, and promises to refine the comprehensive clinical management of stage III CM patients.
authors.affiliation: Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy. lsigalotti@cro.it
authors.forename: Luca
authors.initials: L
authors.lastname: Sigalotti
authors.forename: Alessia
authors.initials: A
authors.lastname: Covre
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Fratta
authors.forename: Giulia
authors.initials: G
authors.lastname: Parisi
authors.forename: Paolo
authors.initials: P
authors.lastname: Sonego
authors.forename: Francesca
authors.initials: F
authors.lastname: Colizzi
authors.forename: Sandra
authors.initials: S
authors.lastname: Coral
authors.forename: Samuele
authors.initials: S
authors.lastname: Massarut
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D019175:DNA Methylation; D017931:DNA Primers; D005260:Female; D016678:Genome; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D017931:DNA Primers