Role of p14(ARF) and p15(INK4B) promoter methylation in patients with lung cancer: a systematic meta-analysis

BACKGROUND: The cyclin-dependent kinase inhibitors p14(ARF) and p15(INK4B) are tumor suppressor genes that have been reported to be silenced through promoter methylation in many human cancers. However, the strength of association between p14(ARF) or p15(INK4B) promoter methylation and lung cancer remains unclear. Thus, we first determined whether p14(ARF) and p15(INK4B) promoter methylation played a key role in the carcinogenesis of lung cancer. METHODS: Eligible studies were selected from the online electronic databases. The pooled odds ratios or hazard ratios and 95% confidence intervals were calculated and summarized. RESULTS: Finally, 12 studies with 625 lung cancer samples and 488 nontumor samples were included under the fixed-effects model. The pooled odds ratio showed that p14(ARF) promoter methylation was observed to be significantly higher in non-small-cell lung cancer (NSCLC) than in nontumor samples (P<0.001). No significant correlation was found between p15(INK4B) promoter methylation and lung cancer (P=0.27). Subgroup analysis of ethnicity revealed that p14(ARF) promoter methylation was significantly related to the risk of NSCLC in Asian and Caucasian populations. Subgroup analysis of sample type demonstrated that p14(ARF) promoter methylation was correlated with the risk of NSCLC in tissue samples (P<0.001), but not in bronchoalveolar lavage fluid and blood samples. P14(ARF) promoter methylation from one study was not significantly correlated with overall survival of patients with NSCLC. Promoter methylation of p14(ARF) and p15(INK4B) was not correlated with clinicopathological characteristics, such as gender status, smoking status, tumor differentiation, and tumor stage (P>0.05). CONCLUSION: Our findings suggested that p14(ARF) promoter methylation may play an important role in the carcinogenesis of lung cancer, but not p15(INK4B) promoter methylation. Promoter methylation of p14(ARF) and p15(INK4B) was not associated with clinicopathological parameters. However, more extensive large-scale studies are essential to further validate our study.