title: Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy.
abstract: OBJECTIVE
  Currently, no validated blood-based assays accurately predict treatment response or outcome in melanoma patients. We hypothesized that methylation of tumor-related genes detected in serum DNA could predict disease outcome and therapeutic response in patients receiving concurrent biochemotherapy (BC) for metastatic melanoma.
  
  
  METHODS
  American Joint Committee on Cancer stage IV melanoma patients (N = 50) had blood drawn before administration of BC. Patients (n = 47) were classified as BC responders or nonresponders. Responders (n = 23) demonstrated a complete or partial response following BC; nonresponders (n = 24) demonstrated progressive disease. Hypermethylation of Ras association domain family 1 (RASSF1A), retinoic acid receptor-beta2 (RAR-beta2), and O6-methylguanine DNA methyltransferase (MGMT) genes were assessed by methylation-specific polymerase chain reaction.
  
  
  RESULTS
  Circulating methylated RASSF1A was significantly less frequent for responders (three of 23 patients; 13%) than nonresponders (10 of 24 patients; 42%; P = .028). Patients with RASSF1A, RAR-beta2, or at least one serum methylated gene had significantly worse overall survival than patients with no methylated genes (log-rank, P = .013, .021, and .01, respectively). Methylated RASSF1A was the only factor that significantly correlated with overall survival and BC response (risk ratio, 2.38; 95% CI, 1.16 to 4.86; P = .018; odds ratio = 0.21; 95% CI, 0.05 to 0.90; P = .036).
  
  
  CONCLUSIONS
  Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA.
authors.forename: Takuji
authors.initials: T
authors.lastname: Mori
authors.forename: Steven J
authors.initials: SJ
authors.lastname: O'Day
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Umetani
authors.forename: Steve R
authors.initials: SR
authors.lastname: Martinez
authors.forename: Minoru
authors.initials: M
authors.lastname: Kitago
authors.forename: Kazuo
authors.initials: K
authors.lastname: Koyanagi
authors.forename: Christine
authors.initials: C
authors.lastname: Kuo
authors.forename: Teh-Ling
authors.initials: TL
authors.lastname: Takeshima
authors.forename: Robert
authors.initials: R
authors.lastname: Milford
authors.forename: He-Jing
authors.initials: HJ
authors.lastname: Wang
authors.forename: Vu D
authors.initials: VD
authors.lastname: Vu
authors.forename: Sandy L
authors.initials: SL
authors.lastname: Nguyen
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007376:Interleukin-2 / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014747:Vinblastine / Q000008:administration & dosage
chemical_list: D004273:DNA, Neoplasm; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; C411762:RASSF1 protein, human; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D014747:Vinblastine; D003606:Dacarbazine; D002945:Cisplatin; D000077204:Temozolomide