Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy.
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.
Mori
Takuji
T
Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA.
O'Day
Steven J
SJ
Umetani
Naoyuki
N
Martinez
Steve R
SR
Kitago
Minoru
M
Koyanagi
Kazuo
K
Kuo
Christine
C
Takeshima
Teh-Ling
TL
Milford
Robert
R
Wang
He-Jing
HJ
Vu
Vu D
VD
Nguyen
Sandy L
SL
Hoon
Dave S B
DS
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
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