Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion

Hideki Katayama, Akio Hiraki, Keisuke Aoe, Keiichi Fujiwara, Keitaro Matsuo, Tadashi Maeda, Tomoyuki Murakami, Shinichi Toyooka, Kazuro Sugi, Hiroshi Ueoka, Mitsune Tanimoto

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Accumulating evidence implicates epigenetic changes such as hypermethylation in carcinogenesis. We investigated whether DNA methylation of 5 tumor suppressor genes in pleural fluid samples could aid in diagnosis of malignant effusion. In samples from 47 patients with malignant pleural effusions and 34 with nonmalignant effusions, we used a methylation-specific polymerase chain reaction to detect aberrant hypermethylation of the promoters of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), p16 INK4a, ras association domain family 1A (RASSF1A), apoptosis-related genes, death-associated protein kinase (DAPK), and retinoic acid receptor β (RARβ). Promoter hypermethylation was associated with malignant effusion for MGMT (Odds ratio (OR) = ∞), p16INK4a (OR = ∞), RASSF1A (OR = 13.8; CI, 1.71-112), and RARβ (OR = 3.17; CI, 1.10-9.11), but not for DAPK. Instead, DAPK methylation was associated with the length of smoking (p <0.05). Patients with hypermethylation of MGMT, p16 INK4a, RASSF1A or RARβ were 5.68 times more likely to have malignant effusions than patients without methylation (p = 0.008). Methylations per patient were more numerous for lung cancer than nonmalignant pulmonary disease (0.915 vs. 0.206, p <0.001). Sensitivity, specificity, and positive predictive value of methylation in one or more genes for diagnosis of malignant effusion were 59.6%, 79.4%, and 80.0% respectively. In conclusion, aberrant promoter methylation of tumor suppressor genes in pleural fluid DNA could be a valuable diagnostic marker for malignant pleural effusion.

Original languageEnglish
Pages (from-to)2191-2195
Number of pages5
JournalInternational Journal of Cancer
Volume120
Issue number10
DOIs
Publication statusPublished - May 15 2007

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Malignant Pleural Effusion
Methylation
Death-Associated Protein Kinases
Retinoic Acid Receptors
DNA
Methyltransferases
Odds Ratio
Tumor Suppressor Genes
Genes
DNA Methylation
Epigenomics
DNA Repair
Lung Diseases
Lung Neoplasms
Carcinogenesis
Smoking
Apoptosis
Sensitivity and Specificity
Polymerase Chain Reaction

Keywords

  • DAPK
  • Malignant pleural effusion
  • MGMT
  • p16
  • RARβ
  • RASSF1A

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion. / Katayama, Hideki; Hiraki, Akio; Aoe, Keisuke; Fujiwara, Keiichi; Matsuo, Keitaro; Maeda, Tadashi; Murakami, Tomoyuki; Toyooka, Shinichi; Sugi, Kazuro; Ueoka, Hiroshi; Tanimoto, Mitsune.

In: International Journal of Cancer, Vol. 120, No. 10, 15.05.2007, p. 2191-2195.

Research output: Contribution to journalArticle

Katayama, H, Hiraki, A, Aoe, K, Fujiwara, K, Matsuo, K, Maeda, T, Murakami, T, Toyooka, S, Sugi, K, Ueoka, H & Tanimoto, M 2007, 'Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion', International Journal of Cancer, vol. 120, no. 10, pp. 2191-2195. https://doi.org/10.1002/ijc.22576
Katayama, Hideki ; Hiraki, Akio ; Aoe, Keisuke ; Fujiwara, Keiichi ; Matsuo, Keitaro ; Maeda, Tadashi ; Murakami, Tomoyuki ; Toyooka, Shinichi ; Sugi, Kazuro ; Ueoka, Hiroshi ; Tanimoto, Mitsune. / Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion. In: International Journal of Cancer. 2007 ; Vol. 120, No. 10. pp. 2191-2195.
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abstract = "Accumulating evidence implicates epigenetic changes such as hypermethylation in carcinogenesis. We investigated whether DNA methylation of 5 tumor suppressor genes in pleural fluid samples could aid in diagnosis of malignant effusion. In samples from 47 patients with malignant pleural effusions and 34 with nonmalignant effusions, we used a methylation-specific polymerase chain reaction to detect aberrant hypermethylation of the promoters of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), p16 INK4a, ras association domain family 1A (RASSF1A), apoptosis-related genes, death-associated protein kinase (DAPK), and retinoic acid receptor β (RARβ). Promoter hypermethylation was associated with malignant effusion for MGMT (Odds ratio (OR) = ∞), p16INK4a (OR = ∞), RASSF1A (OR = 13.8; CI, 1.71-112), and RARβ (OR = 3.17; CI, 1.10-9.11), but not for DAPK. Instead, DAPK methylation was associated with the length of smoking (p <0.05). Patients with hypermethylation of MGMT, p16 INK4a, RASSF1A or RARβ were 5.68 times more likely to have malignant effusions than patients without methylation (p = 0.008). Methylations per patient were more numerous for lung cancer than nonmalignant pulmonary disease (0.915 vs. 0.206, p <0.001). Sensitivity, specificity, and positive predictive value of methylation in one or more genes for diagnosis of malignant effusion were 59.6{\%}, 79.4{\%}, and 80.0{\%} respectively. In conclusion, aberrant promoter methylation of tumor suppressor genes in pleural fluid DNA could be a valuable diagnostic marker for malignant pleural effusion.",
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