Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy

Takuji Mori, Steven J. O'Day, Naoyuki Umetani, Steve R. Martinez, Minoru Kitago, Kazuo Koyanagi, Christine Kuo, Teh Ling Takeshima, Robert Milford, He Jing Wang, Vu D. Vu, Sandy L. Nguyen, Dave S B Hoon

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Patients and 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-β2 (RAR-β2), 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-β2, 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). Conclusion: Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.

Original languageEnglish
Pages (from-to)9351-9358
Number of pages8
JournalJournal of Clinical Oncology
Volume23
Issue number36
DOIs
Publication statusPublished - 2005
Externally publishedYes

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Melanoma
DNA
Serum
Retinoic Acid Receptors
Methylation
Genes
Odds Ratio
Survival
Methyltransferases
Neoplasms
Polymerase Chain Reaction
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy. / Mori, Takuji; O'Day, Steven J.; Umetani, Naoyuki; Martinez, Steve R.; Kitago, Minoru; Koyanagi, Kazuo; Kuo, Christine; Takeshima, Teh Ling; Milford, Robert; Wang, He Jing; Vu, Vu D.; Nguyen, Sandy L.; Hoon, Dave S B.

In: Journal of Clinical Oncology, Vol. 23, No. 36, 2005, p. 9351-9358.

Research output: Contribution to journalArticle

Mori, T, O'Day, SJ, Umetani, N, Martinez, SR, Kitago, M, Koyanagi, K, Kuo, C, Takeshima, TL, Milford, R, Wang, HJ, Vu, VD, Nguyen, SL & Hoon, DSB 2005, 'Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy', Journal of Clinical Oncology, vol. 23, no. 36, pp. 9351-9358. https://doi.org/10.1200/JCO.2005.02.9876
Mori, Takuji ; O'Day, Steven J. ; Umetani, Naoyuki ; Martinez, Steve R. ; Kitago, Minoru ; Koyanagi, Kazuo ; Kuo, Christine ; Takeshima, Teh Ling ; Milford, Robert ; Wang, He Jing ; Vu, Vu D. ; Nguyen, Sandy L. ; Hoon, Dave S B. / Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 36. pp. 9351-9358.
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title = "Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy",
abstract = "Purpose: 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. Patients and 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-β2 (RAR-β2), 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-β2, 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). Conclusion: Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.",
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T1 - Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy

AU - Mori, Takuji

AU - O'Day, Steven J.

AU - Umetani, Naoyuki

AU - Martinez, Steve R.

AU - Kitago, Minoru

AU - Koyanagi, Kazuo

AU - Kuo, Christine

AU - Takeshima, Teh Ling

AU - Milford, Robert

AU - Wang, He Jing

AU - Vu, Vu D.

AU - Nguyen, Sandy L.

AU - Hoon, Dave S B

PY - 2005

Y1 - 2005

N2 - Purpose: 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. Patients and 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-β2 (RAR-β2), 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-β2, 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). Conclusion: Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.

AB - Purpose: 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. Patients and 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-β2 (RAR-β2), 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-β2, 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). Conclusion: Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.

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