Association between P16INK4a Promoter Methylation and Ovarian Cancer: A Meta-Analysis of 12 Published Studies

Abstract

BackgroundOvarian cancer is the primary cause of death in women diagnosed with gynecological malignancies worldwide. Absence of early symptoms prevents prompt diagnosis or successful therapeutic intervention. P16INK4a is a well-known tumor suppressor gene (TSG). Aberrant methylation of TSG promoter is an important epigenetic silencing mechanism leading to ovarian cancer progression. Studies have reported differences in methylation frequencies of the p16INK4a promoter between ovarian cancer and the corresponding control group. However, the association between p16INK4a promoter methylation and ovarian cancer remains unclear and controversial. Therefore, a meta-analysis was conducted to clarify the relationship between p16INK4a promoter methylation and ovarian cancer.MethodsPubMed, Web of Science, EMBASE and CNKI were searched to identify eligible studies for the evaluation of the association between p16INK4a promoter methylation and ovarian cancer. Odds ratio (ORs) and 95% confidence intervals (95%CI) were calculated to determine the strength of association between p16INK4a promoter methylation and ovarian cancer.ResultsA total of 612 ovarian cancer patients and 289 controls from 12 eligible studies were included in the meta-analysis. Overall, a significant association was observed between p16INK4a methylation status and ovarian cancer risk using a fixed-effects model (OR = 2.02, 95% CI = 1.39–2.94).ConclusionThe results of our meta-analysis show that aberrant methylation of p16INK4a promoter was significantly associated with ovarian cancer. It may represent a promising molecular marker to monitor the disease and provides new insights into the treatment of human ovarian cancer.

Quantitative assessment of aberrant <em>P16^INK4a</em> methylation in ovarian cancer: a meta-analysis based on literature and TCGA datasets

“…Compared with previous meta-analyses,31,32 our meta-analysis had several improvements. First, the development of ovarian cancer is a multistep procedure involving normal tissues, benign disease, LMP or borderline tumor, and malignant tumor 20.…”

“…P16 INK4a , which resembles classic TSGs such as P53 , is an important negative regulator of cell growth and proliferation 16. It has been synthetically evaluated for aberrant P16 INK4a methylation in numerous cancers,51–54 including ovarian cancer 31,32. Considering the conflicting conclusions in two meta-analyses and the lack of comprehensive assessment on the role of methylated P16 INK4a in ovarian cancer, we performed an adaptive synthesized analysis to investigate the relationships between P16 INK4a promoter methylation and ovarian cancer risk, as well as clinicopathological features and prognostic value in ovarian cancer.…”

Methylation and ovarian cancer: Can DNA methylation be of diagnostic use? (Review)

“…The other is the gene P16INK4a. A meta-study from 2016, including 612 OC patients and 289 controls from 12 studies, confirmed that P16INK4a promoter hypermethylation is found regularly in OC while rarely found in controls (21).…”

“…One of the earliest proofs that erroneous DNA methylation is directly involved in carcinogenesis came in 1994, when Herman et al showed that the tumor suppressor gene VHL might be silenced by hypermethylation of its promotor in some cases of renal carcinomas (19). Since then, numerous similar studies has shown that promotor hypermethylation is a widespread mechanism for silencing of tumor suppressor genes in human cancers, and it is estimated to be as common as mutation (20,21). Cancer related DNA methylation is often observed earlier than the actual neoplastic transformation, and it has been suggested that DNA methylation is a primary link between environment and cancer, as there seems to be a connection between lifestyle and cancer related DNA methylation in un-symptomatic persons (22,23).…”

Searching for new biomarkers in ovarian cancer patients: Rationale and design of a retrospective study under the Mermaid III project

“…However, erroneous changes in DNA methylation-patterns are often seen in carcinogenesis [37] . Increasing levels of DNA methyltransferase and localized hypermethylation has been observed, especially in the promotors of tumor suppressors [38] , [39] . However, reduced methylation of oncogene promoters or genome wide hypomethylation, resulting in chromosome instability, has also been observed in cancer [40] , [41] .…”