A Systematic Analysis of the Relationship of CDH13 Promoter Methylation and Breast Cancer Risk and Prognosis

Abstract

Background: CDH13 (cadherin 13) is a special cadherin cell adhesion molecule, and the methylation of its promoter causes inactivation in a considerable number of human cancers. To explore the association between CDH13 promoter methylation and breast cancer risk and prognosis, we systematically integrated published articles to investigate the diagnostic performance of the CDH13 methylation test for breast cancer. An independent DNA methylation microarray dataset from The Cancer Genome Atlas project (TCGA) project was used to validate the results of the meta-analysis.

Methods: The relevant literature was searched using the PubMed, Cochrane Library, Web of Science and Google Scholar databases for articles published in English up to May 2015. Data were analyzed using random effect or fixed effect models. The effect sizes were estimated by measuring an odds ratio (OR) or hazard ratio (HR) with a 95% confidence interval (CI). A chi-squared based Q test and sensitivity analysis were performed to examine the between-study heterogeneity and the contribution of single studies to the final results, respectively. Funnel plots were constructed to evaluate publication bias.

Results: Seven hundred and twenty-six breast tumor samples and 422 controls were collected from 13 published studies. The data from the TCGA set include both tumor and normal samples. A significant association was observed between CDH13 promoter methylation and breast cancer, with an aggregated OR equal to 13.73 (95%CI: 8.09~23.31, z = 9.70, p<0.0001) as measured using the fixed effect model and 14.23 (95%CI: 5.06~40.05, z = 5.03, p<0.0001) as measured using a random effect model. The HR values were calculated as 0.77 (95%CI: 0.27~2.21, z = -0.49, p = 0.622) and 0.38 (95%CI: 0.09~1.69, z = -1.27, p = 0.20) for overall survival (OS) and disease-free survival (DFS), respectively, using the random effect model. This result indicated that breast cancer patients with CDH13 promoter methylation correlated non-significantly with prognosis and is therefore similar to the findings of the TCGA project.

Conclusions: The methylation status of CDH13 promoter was strongly associated with breast cancer risk. However, CDH13 promoter methylation was not significantly related to the OS and DFS of breast cancer and may have limited prognostic value for breast cancer patients.

Fig 1. Flow chart of study identification.

Fig 2. Combined estimates for the association between CDH13 promoter methylation and breast cancer with forest plot.

Author, year, and country of the studies, methylated (M) and total number of samples (T) in case and control, and combined odds ratio (OR) with 95% confidence region were labeled in the right column of the figure. The DerSimonian-Laird estimator and Mantel-Haenszel method were selected to conduct combination estimation for the random effects model and fixed effects model, respectively.

Fig 3. Subgroup meta-analysis for the relationship between CDH13 promoter methylation and breast cancer.

(A, B). Subgroup meta-analysis based on race and sample by random effects model and fixed effects model, respectively.

Fig 4. Funnel plot for publication bias test and sensitivity analysis of the summary odds ratio coefficients on the relationships between CDH13 methylation and breast cancer patients.

Fig 5. The relationships of CDH13 methylation with TCGA probe, sample source and survival curve of breast cancer in the TCGA data.

(A). Different TCGA probe for 450 K datasets shows the relationship of CDH13 methylation and breast cancer risk (N_Tumor = 699, N_Normal = 96, respectively). (C). The t-test indicates significant differences in blood (N = 444) and tissue (N = 120) samples compared to normal tissue (N = 96). (B, D). Association of patient survival and CDH13 methylation status by Kaplan-Meier method. Red dotted line indicates β = 0.3.

Fig 6. Different racial types affecting the OR of the CDH13 methylation to the risk of breast cancer in the TCGA data.

(A-C). The beanplot demonstrates that different racial types affect the CDH13 methylation to the risk of breast cancer in data from TCGA breast cancer datasets. The number of tumor patients is 524, 34, 101 in White, Asian and Black or African American people, respectively. Black dotted line indicates β = 0.3. The differences are significant by t-test.