Cigarette smoking and p16INK4α gene promoter hypermethylation in non-small cell lung carcinoma patients: a meta-analysis

Abstract

Background: Aberrant methylation of promoter DNA and transcriptional repression of specific tumor suppressor genes play an important role in carcinogenesis. Recently, many studies have investigated the association between cigarette smoking and p16(INK4α) gene hypermethylation in lung cancer, but could not reach a unanimous conclusion.

Methods and findings: Nineteen cross-sectional studies on the association between cigarette smoking and p16(INK4α) methylation in surgically resected tumor tissues from non-small cell lung carcinoma (NSCLC) patients were identified in PubMed database until June 2011. For each study, a 2×2 cross-table was extracted. In total, 2,037 smoker and 765 nonsmoker patients were pooled with a fixed-effects model weighting for the inverse of the variance. Overall, the frequency of p16(INK4α) hypermethylation was higher in NSCLC patients with smoking habits than that in non-smoking patients (OR = 2.25, 95% CI = 1.81-2.80). The positive association between cigarette smoking and p16(INK4α) hypermethylation was similar in adenocarcinoma and squamous-cell carcinoma. In the stratified analyses, the association was stronger in Asian patients and in the studies with larger sample sizes.

Conclusion: Cigarette smoking is positively correlated to p16(INK4α) gene hypermethylation in NSCLC patients.

Figure 1. Flow diagram of the stepwise selection from associated studies.

Figure 2. Meta-analysis of cigarette smoking and p16^INK4α methylation in all NSCLC patients.

Figure 3. Meta-analysis of cigarette smoking and p16^INK4α methylation in lung adenocarcinoma patients.

Figure 4. Meta-analysis of cigarette smoking and p16^INK4α methylation in NSCLC patients stratified by sample size.

A: sample size >100. B: sample size <100. Stratification by sample size showed a stronger association in studies with a relatively larger sample size.

Figure 5. Meta-analysis of cigarette smoking and p16^INK4α methylation in NSCLC patient stratified by study region.

A: Asian studies. B: North American studies. The association between cigarette smoking and p16^INK4α methylation tended to be stronger in Asian studies compared to the North American studies.

Figure 6. Begg's funnel plot for visual assessment of the presence of publication bias for all studies included in the meta-analysis (each study is represented by an open circle).