Aberrant promoter methylation of multiple genes in non-small cell lung cancers

S. Zöchbauer-Müller, K. M. Fong, A. K. Virmani, J. Geradts, A. F. Gazdar, J. D. Minna

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Abstract

Aberrant methylation of CpG islands acquired in tumor cells in promoter regions is one method for loss of gene function. We determined the frequency of aberrant promoter methylation (referred to as methylation) of the genes retinoic acid receptor β-2 (RARβ), tissue inhibitor of metalloproteinase 3 (TIMP-3), p16INK4α, O6-methylguanine-DNA-methyltransferase (MGMT), death-associated protein kinase (DAPK), E-cadherin (ECAD), p14ARF, and glutathione S-transferase P1 (GSTP1) in 107 resected primary non-small cell lung cancers (NSCLCs) and in 104 corresponding nonmalignant lung tissues by methylation-specific PCR. Methylation in the tumor samples was detected in 40% for RARβ, 26% for TIMP-3, 25% for p16INK4α, 21% for MGMT, 19% for DAPK, 18% for ECAD, 8% for p14ARF, and 7% for GSTP1, whereas it was not seen in the vast majority of the corresponding nonmalignant tissues. Moreover, p16INK4α methylation was correlated with loss of p16INK4α expression by immunohistochemistry. A total of 82% of the NSCLCs had methylation of at least one of these genes; 37% of the NSCLCs had one gene methylated, 22% of the NSCLCs had two genes methylated, 13% of the NSCLCs had three genes methylated, 8% of the NSCLCs had four genes methylated, and 2% of the NSCLCs had five genes methylated. Methylation of these genes was correlated with some clinicopathological characteristics of the patients. In comparing the methylation patterns of tumors and nonmalignant lung tissues from the same patients, there were many discordancies where the genes methylated in nonmalignant tissues were not methylated in the corresponding tumors. This suggests that the methylation was occurring as a preneoplastic change. We conclude that these findings confirm in a large sample that methylation is a frequent event in NSCLC, can also occur in smoking-damaged nonmalignant lung tissues, and may be the most common mechanism to inactivate cancer-related genes in NSCLC.

Original languageEnglish (US)
Pages (from-to)249-255
Number of pages7
JournalCancer Research
Volume61
Issue number1
StatePublished - Jan 1 2001

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Non-Small Cell Lung Carcinoma
Methylation
Genes
Death-Associated Protein Kinases
Tumor Suppressor Protein p14ARF
Tissue Inhibitor of Metalloproteinase-3
Retinoic Acid Receptors
Methyltransferases
Cadherins
Glutathione Transferase
Lung
Neoplasms
CpG Islands
Neoplasm Genes
DNA
Genetic Promoter Regions
Smoking
Immunohistochemistry
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zöchbauer-Müller, S., Fong, K. M., Virmani, A. K., Geradts, J., Gazdar, A. F., & Minna, J. D. (2001). Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Research, 61(1), 249-255.

Aberrant promoter methylation of multiple genes in non-small cell lung cancers. / Zöchbauer-Müller, S.; Fong, K. M.; Virmani, A. K.; Geradts, J.; Gazdar, A. F.; Minna, J. D.

In: Cancer Research, Vol. 61, No. 1, 01.01.2001, p. 249-255.

Research output: Contribution to journalArticle

Zöchbauer-Müller, S, Fong, KM, Virmani, AK, Geradts, J, Gazdar, AF & Minna, JD 2001, 'Aberrant promoter methylation of multiple genes in non-small cell lung cancers', Cancer Research, vol. 61, no. 1, pp. 249-255.
Zöchbauer-Müller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD. Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Research. 2001 Jan 1;61(1):249-255.
Zöchbauer-Müller, S. ; Fong, K. M. ; Virmani, A. K. ; Geradts, J. ; Gazdar, A. F. ; Minna, J. D. / Aberrant promoter methylation of multiple genes in non-small cell lung cancers. In: Cancer Research. 2001 ; Vol. 61, No. 1. pp. 249-255.
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abstract = "Aberrant methylation of CpG islands acquired in tumor cells in promoter regions is one method for loss of gene function. We determined the frequency of aberrant promoter methylation (referred to as methylation) of the genes retinoic acid receptor β-2 (RARβ), tissue inhibitor of metalloproteinase 3 (TIMP-3), p16INK4α, O6-methylguanine-DNA-methyltransferase (MGMT), death-associated protein kinase (DAPK), E-cadherin (ECAD), p14ARF, and glutathione S-transferase P1 (GSTP1) in 107 resected primary non-small cell lung cancers (NSCLCs) and in 104 corresponding nonmalignant lung tissues by methylation-specific PCR. Methylation in the tumor samples was detected in 40{\%} for RARβ, 26{\%} for TIMP-3, 25{\%} for p16INK4α, 21{\%} for MGMT, 19{\%} for DAPK, 18{\%} for ECAD, 8{\%} for p14ARF, and 7{\%} for GSTP1, whereas it was not seen in the vast majority of the corresponding nonmalignant tissues. Moreover, p16INK4α methylation was correlated with loss of p16INK4α expression by immunohistochemistry. A total of 82{\%} of the NSCLCs had methylation of at least one of these genes; 37{\%} of the NSCLCs had one gene methylated, 22{\%} of the NSCLCs had two genes methylated, 13{\%} of the NSCLCs had three genes methylated, 8{\%} of the NSCLCs had four genes methylated, and 2{\%} of the NSCLCs had five genes methylated. Methylation of these genes was correlated with some clinicopathological characteristics of the patients. In comparing the methylation patterns of tumors and nonmalignant lung tissues from the same patients, there were many discordancies where the genes methylated in nonmalignant tissues were not methylated in the corresponding tumors. This suggests that the methylation was occurring as a preneoplastic change. We conclude that these findings confirm in a large sample that methylation is a frequent event in NSCLC, can also occur in smoking-damaged nonmalignant lung tissues, and may be the most common mechanism to inactivate cancer-related genes in NSCLC.",
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