Background
Ovarian cancer, the most lethal tumor in gynecologic cancers, is the fifth most cause of cancer-related deaths among women. According to cancer statistics, approximately 21,290 women will be diagnosed and 14,180 will die due to ovarian cancer in the United States in 2015 [
1]. Among ovarian cancer, serous ovarian carcinoma is the most common histotype and only less than 20 % of ovarian cancer can be detected early due to the lack of effective early detection and accurate diagnosis methods [
2]. More than 80 % of ovarian cancer patients at advanced stages relapse [
3]. While the overall 5-year survival rate is only 31 % [
4].
Epigenetic alterations (DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs) are identified to be strongly associated with cancer [
5]. DNA methylation is an important mechanism of epigenetic variability involved in gene expression, which plays key roles in the development of cancer [
6‐
8]. Aberrant methylation of CpG islands of the promoter regions is the major alternative to accomplish tumor suppressor gene (TSG) silencing [
9‐
11].
CDH1, a tumor suppressor gene, also called as epithelial cadherin (E-cadherin) and cadherin-1, is located on 16q23 [
12].
CDH1, a member of the cadherin family, plays an important role in epithelial cell-cell adhesion and in maintaining normal tissue architecture [
13]. The reduction of
CDH1 expression may involve in invasion and metastasis of several cancers [
13‐
15].
However, the association between CDH1 promoter methylation and ovarian cancer remains to be certified. In this study, we performed a meta-analysis to evaluate the relationships between ovarian cancer tissues and nonmalignant ovarian tissues and Low malignant potential (LMP) tumor tissues. In addition, we also assess the relationship between CDH1 promoter methylation and clinicopathological features in ovarian cancer.
Methods
Literature search and selection criteria
A systematic literature search was performed in PubMed, EMBASE, Cochrane Library, CNKI and Wanfang databases, using the following keywords and search items: (CDH1 OR E-cadherin OR cadherin 1) AND (ovarian OR ovary) AND (cancer OR carcinoma OR tumor) AND methylation. The search updated until December 25. 2015. Moreover, a manual search of the references was also conducted to identify the potentially additional articles.
For eligible studies, studies must meet the following criteria: (1) all patients were diagnosed for primary ovarian cancer; (2) the study was about CDH1 promoter methylation and ovarian cancer; (3) study must have sufficient data about the frequencies of CDH1 promoter methylation to assess to the relationship between CDH1 promoter methylation and ovarian cancer; (4) only the most recent paper or the most complete one was selected to avoid duplicated publications. Study was excluded if it did not meet the inclusion criteria above.
For each eligible study, the following information were extracted: the first author’s name, publication year, methylation region, country, ethnicity, the method of methylation detection, type of control, the number of methylation, the sample size, clinicopathological parameters, such as the number of tumor stage, the number of tumor histology, etc. Nonmalignant ovarian tissues were defined as controls, including benign disease, normal tissues or adjacent normal tissues. Low malignant potential (LMP) tumors were also served as a single control group.
Statistical analysis
Meta-analysis was conducted using the STATA software (version 12.0, Stata Corporation, College Station, TX, USA). The pooled odds ratios (OR) and 95 % confidence interval (95 % CI) were calculated to evaluate the association between
CDH1 promoter methylation and ovarian cancer risk. Between-study heterogeneity was examined using the Cochran’s Q test and I
2 statistic [
16]. If I
2 < 50 % and
p ≥ 0.1 were considered as a measure of lack heterogeneity, a fixed-effects model was applied; otherwise, the random-effects model was used [
17,
18]. Publication bias was assessed by using Egger’s linear regression test [
19].
Discussion
The gene epigenomic regulation of initiation and progression of cancer has two essential components of the molecular mechanism, which are the hypermethylation of tumor suppressor genes and hypomethylation of oncogenes [
27‐
29]. The CpG islands methylation of the promoter is an important reason for loss of gene expression, which can lead to the transcription repression of the gene [
30]. Inactivation of
CDH1 by promoter hypermethylation has been observed in several types of cancers, including breast cancer, ovarian cancer and gastric cancer [
31‐
33]. However, the frequency of
CDH1 promoter methylation was inconsistent. Montavon et al. reported that the frequency of
CDH1 promoter methylation was 21.8 % and 20 % in ovarian cancer and nonmalignant ovarian disease respectively [
34]. Rathi et al. reported that the frequency of
CDH1 promoter methylation was 28.6 % and 5 % in ovarian cancer tissues and nonmalignant tissues respectively [
35]. So the current meta-analysis was performed to identify the association between
CDH1 promoter methylation and ovarian cancer risk.
A total of 9 studies including 485 cancer tissues and 255 nonmalignant tissues were involved in our study. CDH1 promoter methylation had an increased risk in cancer tissues (OR = 8.71, 95 % CI = 4.87 - 15.58, P < 0.001) in comparison with nonmalignant tissues. Subgroup analysis based on the ethnicity suggested that the CDH1 promoter methylation status was significantly increased risks of ovarian cancer in Asian population and Caucasian population (OR = 13.20, 95 % CI = 6.12 - 28.45; OR = 3.84, 95 % CI = 1.52 - 9.74; respectively). The OR value of Asian population subgroup (OR = 13.20) was higher than that in Caucasian population subgroup (OR = 3.84), suggesting that Asian population can be more susceptible to CDH1 promoter methylation. However, the results should be interpreted with caution as only small subjects were included in subgroup analyses. No significant association was observed between ovarian cancer and LMP tumor (P = 0.096), including a total of 109 ovarian cancer patients and 37 low malignant tumor patients.
We further evaluated the relationships of CDH1 promoter methylation with clinicopathological features, such as tumor histology and tumor stage. Our findings indicated that the CDH1 promoter methylation status was not significantly associated with tumor stage and histology. Publication bias was not detected by Egger’s test (all P > 0.05).
The current study had some limitations. Firstly, the search strategy was restricted to articles published in English or Chinese. Secondly, the total sample size was not sufficient larger (less than 1000) [
36], our results may be lack vigorous power to evaluate the associations between
CDH1 promoter methylation and ovarian cancer risk. Thirdly, based on the limitation of insufficient data, we did not study the
CDH1 promoter methylation status in other clinicopathological features, such as tumor grade, sex status and age etc. Therefore, a meta-analysis including more studies with larger sample size should be necessary to confirm the results in the future.
Conclusion
CDH1 promoter methylation is significantly associated with ovarian cancer risk. In addition, the potential association on CDH1 promoter methylation and some clinicopathological features are still unclear due to the limitation of studies and sample size.
Ethics approval and consent to participate
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Availability of data and material
All data is available in this paper.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
WW and QW contributed to the conception and design. QW, BW, YMZ, and WW contributed to completion of articles, the data extraction, data calculated and design of figures and tables. All the authors approved the final manuscript.