Aberrant methylation of the CDKN2a/p16INK4a gene promoter region in preinvasive bronchial lesions: a prospective study in high-risk patients without invasive cancer

Our plain-English summary of Aberrant methylation of the CDKN2a/p16INK4a gene promoter region in preinvasive bronchial lesions: a prospective study in high-risk patients without invasive cancer, by A. Lamy, R. Sesboüé, J. Bourguignon, et al (International Journal of Cancer, 2002).

The study

• Authors: A. Lamy, R. Sesboüé, J. Bourguignon, B. Dautréaux, J. Métayer, T. Frébourg, L. Thiberville
• Journal: International Journal of Cancer
• Published: 2002;100(2):189-93
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Among the identified factors involved in malignant transformation, abnormal methylation of the CDKN2A/p16(INK4a) gene promoter has been described as an early event, particularly in bronchial cell cancerization. Precancerous bronchial lesions (n = 70) prospectively sampled during fluorescence endoscopy in a series of 37 patients at high risk for lung cancer were studied with respect to the methylation status of the CDKN2A gene. Methylation-specific polymerase chain reaction was performed on DNA extracted from pure bronchial cell populations derived from biopsies and detection of p16 protein was studied by immunohistochemistry on contiguous parallel biopsies. Aberrant methylation of the CDKN2A gene promoter was found in 19% of preinvasive lesions and its frequency increased with the histologic grade of the lesions. Methylation in at least 1 bronchial site was significantly more frequent in patients with cancer history, although there was no difference in the outcome of patients with or without methylation in bronchial epithelium. The other risk factors studied (tobacco and asbestos exposure) did not influence the methylation status. There was no relationship between CDKN2A methylation and the evolutionary character of the lesions. Our results confirm that abnormal methylation of the CDKN2A gene promoter is an early event in bronchial cell cancerization, which can persist for several years after carcinogen exposure cessation, and show that this epigenetic alteration cannot predict the evolution of precancerous lesions within a 2-year follow-up.

Copyright 2002 Wiley-Liss, Inc.

In plain English

This prospective study in Rouen, France, examined methylation, a chemical change in the CDKN2A/p16INK4a gene's control region, in precancerous airway lesions. The 37 patients were enrolled in 1999 in an early-detection program. Each had smoked at least 30 pack-years, been exposed to asbestos, or had a past ear, nose and throat or lung cancer. None had cancer on imaging. Seventy airway biopsies taken during fluorescence bronchoscopy were studied. Methylation was found in 13 of 70 biopsies (18.6%). The rate rose from 4.6% in normal or inflamed tissue to 50% in the most severe lesions. It occurred in 4 of 14 asbestos-exposed patients (28.6%) and 8 of 23 unexposed patients (34.8%), which the authors called no difference. It was significantly more frequent in patients with a past cancer (9 of 19, 47.4%) than in those without (3 of 18, 16.7%; p = 0.046). Over 19 to 28 months, methylation was not significantly linked to lesions worsening or patients developing cancer. The authors concluded that this change is an early event but did not seem to predict rapid lesion worsening within two years.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective study of bronchial biopsies taken during fluorescence bronchoscopy, with laboratory testing for gene promoter methylation (methylation-specific PCR) and p16 protein staining, and 19 to 28 months of follow-up
• Who was studied: 37 patients in the Early Lung Cancer Detection Program at Rouen University Hospital, France, enrolled February to November 1999. Inclusion required at least 30 pack-years of cigarette smoking, asbestos exposure, or a history of ear, nose and throat or lung cancer. All were radiographically free of cancer. 70 bronchial areas were biopsied.
• Exposure: Asbestos fiber exposure (fiber type and dose not specified; 14 of 37 patients exposed), cigarette smoking (at least 30 pack-years as an inclusion criterion; 24 current smokers, 11 ex-smokers, 2 never-smokers), and prior ear, nose and throat or lung cancer
• Main results:
  • Aberrant CDKN2A promoter methylation was found in 13 of 70 biopsies (18.6%).
  • Methylation frequency rose with lesion grade: 4.6% in normal or inflammation biopsies, 25% and 20.8% in low-grade lesions (metaplasia, mild and moderate dysplasia), and 50% in high-grade lesions (severe dysplasia and carcinoma in situ).
  • In a subset of 14 samples tested both ways, methylation status correlated strongly with loss of p16 protein staining in the neighbouring biopsy, with only 2 samples discordant.
  • Among patients, methylation was found in 4 of 14 asbestos-exposed patients (28.6%) and 8 of 23 unexposed patients (34.8%). The authors reported no difference.
  • Methylation was found in 6 of 11 ex-smokers (54.5%) and 6 of 24 current smokers (25%). The authors reported this difference as not significant.
  • Methylation in at least one bronchial site was significantly more frequent in patients with a history of ear, nose and throat or lung cancer (9 of 19, 47.4%) than in those without (3 of 18, 16.7%), p = 0.046.
  • Of 29 lesions followed for 19 to 28 months, 6 progressed to high-grade dysplasia or invasive cancer. Methylation was present in 3 of 6 progressing lesions (50%) and 5 of 23 stable lesions (21.7%), a difference that was not significant.
  • 12 of 37 patients developed invasive cancer during follow-up. 6 of these 12 (50%) had methylation, compared with 24% of patients who did not develop cancer. This difference was not significant (p = 0.115).
• The authors' conclusion: The authors concluded that CDKN2A promoter methylation is a frequent and early event in bronchial cancer, detectable in early lesions of at-risk patients before invasive cancer develops. They suggested it might be considered a marker of exposure, but it did not seem to predict rapid worsening of lesions within a 2-year follow-up.
• Limitations the authors state:
  • Two neighbouring biopsies were used (one for histology, one for methylation testing), and they may have represented different grades of lesion.
  • Cells had to be grown in culture to obtain enough DNA, which could have introduced artifacts. The authors judged this unlikely based on control testing.
  • The finding that methylation did not predict lesion progression needs confirmation over a longer follow-up period.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: CDKN2A, Malignant Transformation, Endoscopy, Lung Cancer, Immunohistochemistry, Epithelium, Asbestos Exposure.

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