The Prognostic Value of p16 Hypermethylation in Cancer: A Meta-Analysis

PLoS One. 2013 Jun 21;8(6):e66587. doi: 10.1371/journal.pone.0066587. Print 2013.


Background: The prognostic value of p16 promoter hypermethylation in cancers has been evaluated for several years while the results remain controversial. We thus performed a systematic review and meta-analysis of studies assessing the impact of p16 methylation on overall survival (OS) and disease-free survival (DFS) to clarify this issue.

Methods: We searched Pubmed, Embase and ISI web of knowledge to identify studies on the prognostic impact of p16 hypermethylation in cancers. A total of 6589 patients from 45 eligible studies were included in the analysis. Pooled hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated to estimate the effect using random-effects model.

Results: The analysis indicated that p16 hypermethylation had significant association with poor OS of non-small cell lung cancer (NSCLC) (HR 1.74, 95% CI: 1.36-2.22) and colorectal cancer (CRC) (HR 1.80; 95% CI 1.27-2.55). Moreover, the significant correlation was present between p16 hypermethylation and DFS of NSCLC (HR 2.04, 95% CI: 1.19-3.50) and head and neck cancer (HR 2.24, 95% CI: 1.35-3.73). Additionally, in the analysis of the studies following REMARK guidelines more rigorously, p16 hypermethylation had unfavorable impact on OS of NSCLC (HR 1.79, 95% CI: 1.35-2.39) and CRC (HR 1.96, 1.16-3.34), and on DFS of NSCLC (HR 2.12, 95% CI: 1.21-3.72) and head and neck cancer (HR 2.24, 95% CI: 1.35-3.73).

Conclusions: p16 hypermethylation might be a predictive factor of poor prognosis in some surgically treated cancers, particularly in NSCLC.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Cyclin-Dependent Kinase Inhibitor p16* / genetics
  • Cyclin-Dependent Kinase Inhibitor p16* / metabolism
  • DNA Methylation*
  • DNA, Neoplasm* / genetics
  • DNA, Neoplasm* / metabolism
  • Disease-Free Survival
  • Female
  • Humans
  • Male
  • Neoplasms* / genetics
  • Neoplasms* / metabolism
  • Neoplasms* / mortality
  • Neoplasms* / surgery
  • Predictive Value of Tests
  • Survival Rate


  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Neoplasm

Grant support

This work was supported by National Natural Science Foundation of China (81000887) and Research Fund for the Doctoral Program of Higher Education of China (20090171120064). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.