Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers

Sabine Zöchbauer-Müller, Stephen Lam, Shinichi Toyooka, Arvind K. Virmani, Kiyomi O. Toyooka, Sonja Seidl, John D. Minna, Adi F. Gazdar

Research output: Contribution to journalArticle

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Abstract

An important method for silencing tumor suppressor genes in cancers is by aberrant methylation (referred to as methylation) of CpG islands in gene promoter regions. In lung cancer, methylation of the genes retinoic acid receptor β-2 (RARβ-2), CDH13 (H-cadherin), p16INK4α (p16), RASSF1A (RAS association domain family I) is frequent. Thus, we investigated methylation of these genes in 4 different types of specimens (oropharyngeal brushes, sputum samples, bronchial brushes and bronchioloalveolar lavage [BAL] samples) of the upper aerodigestive tract epithelium from heavy smokers without evidence of cancer but with morphometric evidence of sputum atypia and compared the frequencies of methylation in the different types of specimens. In addition, we also analyzed sputum samples from 30 never smokers for methylation of these genes. Our major findings are: (i) At least one gene was methylated in one or more specimens from 48% of the smokers. However, methylation was statistically significant less frequently in never smokers compared to smokers. (ii) In general, methylation occurred more frequently in samples from the central airways (sputum, bronchial brushes) compared to the peripheral airways (BAL) and only occasionally in the oropharynx. (iii) RARβ-2 was the most frequently methylated gene, whereas the frequency of methylation for the other genes was lower. (iv) Data from sputum samples and bronchial brushes were comparable. Our findings suggest that detection of methylation should be investigated as an intermediate marker for lung cancer risk assessment and response to chemopreventive regimens.

Original languageEnglish (US)
Pages (from-to)612-616
Number of pages5
JournalInternational Journal of Cancer
Volume107
Issue number4
DOIs
StatePublished - Nov 20 2003

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Methylation
Epithelium
Sputum
Genes
Retinoic Acid Receptors
Therapeutic Irrigation
Lung Neoplasms
CpG Islands
Oropharynx
Tumor Suppressor Genes
Genetic Promoter Regions
Gene Frequency
Neoplasms

Keywords

  • Aberrant methylation
  • Cigarette smoking
  • Lung cancer
  • Methylation-specific PCR
  • Preneoplastic lesion

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zöchbauer-Müller, S., Lam, S., Toyooka, S., Virmani, A. K., Toyooka, K. O., Seidl, S., ... Gazdar, A. F. (2003). Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers. International Journal of Cancer, 107(4), 612-616. https://doi.org/10.1002/ijc.11458

Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers. / Zöchbauer-Müller, Sabine; Lam, Stephen; Toyooka, Shinichi; Virmani, Arvind K.; Toyooka, Kiyomi O.; Seidl, Sonja; Minna, John D.; Gazdar, Adi F.

In: International Journal of Cancer, Vol. 107, No. 4, 20.11.2003, p. 612-616.

Research output: Contribution to journalArticle

Zöchbauer-Müller, S, Lam, S, Toyooka, S, Virmani, AK, Toyooka, KO, Seidl, S, Minna, JD & Gazdar, AF 2003, 'Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers', International Journal of Cancer, vol. 107, no. 4, pp. 612-616. https://doi.org/10.1002/ijc.11458
Zöchbauer-Müller S, Lam S, Toyooka S, Virmani AK, Toyooka KO, Seidl S et al. Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers. International Journal of Cancer. 2003 Nov 20;107(4):612-616. https://doi.org/10.1002/ijc.11458
Zöchbauer-Müller, Sabine ; Lam, Stephen ; Toyooka, Shinichi ; Virmani, Arvind K. ; Toyooka, Kiyomi O. ; Seidl, Sonja ; Minna, John D. ; Gazdar, Adi F. / Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers. In: International Journal of Cancer. 2003 ; Vol. 107, No. 4. pp. 612-616.
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abstract = "An important method for silencing tumor suppressor genes in cancers is by aberrant methylation (referred to as methylation) of CpG islands in gene promoter regions. In lung cancer, methylation of the genes retinoic acid receptor β-2 (RARβ-2), CDH13 (H-cadherin), p16INK4α (p16), RASSF1A (RAS association domain family I) is frequent. Thus, we investigated methylation of these genes in 4 different types of specimens (oropharyngeal brushes, sputum samples, bronchial brushes and bronchioloalveolar lavage [BAL] samples) of the upper aerodigestive tract epithelium from heavy smokers without evidence of cancer but with morphometric evidence of sputum atypia and compared the frequencies of methylation in the different types of specimens. In addition, we also analyzed sputum samples from 30 never smokers for methylation of these genes. Our major findings are: (i) At least one gene was methylated in one or more specimens from 48{\%} of the smokers. However, methylation was statistically significant less frequently in never smokers compared to smokers. (ii) In general, methylation occurred more frequently in samples from the central airways (sputum, bronchial brushes) compared to the peripheral airways (BAL) and only occasionally in the oropharynx. (iii) RARβ-2 was the most frequently methylated gene, whereas the frequency of methylation for the other genes was lower. (iv) Data from sputum samples and bronchial brushes were comparable. Our findings suggest that detection of methylation should be investigated as an intermediate marker for lung cancer risk assessment and response to chemopreventive regimens.",
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