title: Aberrant hypermethylation in primary tumours and sentinel lymph node metastases in paediatric patients with cutaneous melanoma.
abstract: BACKGROUND
  Debate on how to manage paediatric patients with cutaneous melanoma continues, particularly in those with sentinel lymph node (SLN) metastases who are at higher risk of poor outcomes. Management is often based on adult algorithms, although differences in clinical outcomes between paediatric and adult patients suggest that melanoma in paediatric patients differs biologically. Yet, there are no molecular prognostic studies identifying these differences.
  
  
  OBJECTIVE
  We investigated the epigenetic (methylation) regulation of several tumour-related genes (TRGs) known to be significant in adult melanoma progression in histopathology(+) SLN metastases (n = 17) and primary tumours (n = 20) of paediatric patients with melanoma to determine their clinical relevance.
  
  
  METHODS
  Paediatric patients (n = 37; ≤ 21 years at diagnosis) with American Joint Committee on Cancer stage I-III cutaneous melanoma were analysed. Gene promoter methylation of the TRGs RASSF1A, RARβ2, WIF1 and APC was evaluated.
  
  
  RESULTS
  Hypermethylation of RASSF1A, RARβ2, WIF1 and APC was found in 29% (5/17), 25% (4/16), 25% (4/16) and 19% (3/16) of histopathology(+) SLNs, respectively. When matched to adult cutaneous melanomas by Breslow thickness and ulceration, hypermethylation of all four TRGs in SLN(+) paediatric patients with melanoma was equivalent to or less than in adults. With a median follow-up of 55 months, SLN(+) paediatric patients with melanoma with hypermethylation of > 1 TRG vs. ≤ 1 TRG had worse disease-free (P = 0·02) and overall survival (P = 0·02).
  
  
  CONCLUSIONS
  Differences in the methylation status of these TRGs in SLN(+) paediatric and adult patients with melanoma may account for why SLN(+) paediatric patients have different clinical outcomes. SLN biopsy should continue to be performed; within SLN(+) paediatric patients with melanoma, hypermethylation of TRGs can be used to identify a subpopulation at highest risk for poor outcomes who warrant vigilant clinical follow-up.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Huynh
authors.forename: Y
authors.initials: Y
authors.lastname: Takei
authors.forename: C
authors.initials: C
authors.lastname: Kuo
authors.forename: R A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: R
authors.initials: R
authors.lastname: Murali
authors.forename: K
authors.initials: K
authors.lastname: Chong
authors.forename: L
authors.initials: L
authors.lastname: Takeshima
authors.forename: M-S
authors.initials: MS
authors.lastname: Sim
authors.forename: D L
authors.initials: DL
authors.lastname: Morton
authors.forename: R R
authors.initials: RR
authors.lastname: Turner
authors.forename: J F
authors.initials: JF
authors.lastname: Thompson
authors.forename: D S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D007223:Infant; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D055815:Young Adult
chemical_list: C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C485569:WIF1 protein, human; C540966:retinoic acid receptor, beta2, human