Predictive Utility of Circulating Methylated DNA in Serum of Melanoma Patients Receiving Biochemotherapy

• Published in: Journal of clinical oncology Vol. 23; no. 36; pp. 9351 - 9358
• Main Authors: MORI, Takuji, O'DAY, Steven J, VU, Vu D, NGUYEN, Sandy L, HOON, Dave S. B, UMETANI, Naoyuki, MARTINEZ, Steve R, KITAGO, Minoru, KOYANAGI, Kazuo, KUO, Christine, TAKESHIMA, Teh-Ling, MILFORD, Robert, WANG, He-Jing
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 20.12.2005; Lippincott Williams & Wilkins
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cisplatin - administration & dosage; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Dermatology; DNA Methylation; DNA, Neoplasm - blood; Drug Administration Schedule; Female; Humans; Interferon alpha-2; Interferon-alpha - administration & dosage; Interleukin-2 - administration & dosage; Male; Medical sciences; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Middle Aged; Odds Ratio; Predictive Value of Tests; Prognosis; Recombinant Proteins; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Survival Analysis; Tamoxifen - administration & dosage; Temozolomide; Treatment Outcome; Tumor Suppressor Proteins - genetics; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Vinblastine - administration & dosage; Human; Cancerology; DNA; Malignant melanoma; Serum; Malignant tumor; Methylation
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2005.02.9876

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. 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. 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). Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.