Promoter Hypermethylation Of Rar Beta 2, Dapk, Hmlh1, P14, And P15 Is Associated With Progression Of Breast Cancer A Prisma-Compliant Meta-Analysis

Background: Numerous studies have investigated the associations between RAR beta 2, DAPK, hMLH1, p14, and p15 promoter hypermethylation and clinical progression of patients with breast cancer, however the results remained uncertain due to the small sample size. Therefore, we performed a meta-analysis to explore the role of RAR beta 2, DAPK, hMLH1, p14, and p15 promoter hypermethylation in the susceptibility and clinical progression of breast cancer.Methods: Eligible studies were obtained by searching Medicine, Embase, Web of knowledge, and Chinese National Knowledge Infrastructure (CNKI) databases. The odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of RAR beta 2, DARK, hMLH1, p14, and p15 promoter hypermethylation with breast cancer pathogenesis. Trial sequential analysis (TSA) was applied to observe the reliability of pooled results of RAR beta 2 gene, and obtain a conservative required information size (RIS).Results: In primary screened 445 articles, 39 literatures with 4492 breast cancer patients were finally enrolled in the final meta analysis. The results indicated that the frequency of RAR beta 2 promoter hypermethylation in case group was significantly higher than the frequency of control group (OR=7.21, 95% CI=1.54-33.80, P < .05). The RAR beta 2 promoter hypermethylation had a significant association with lymph node metastasis of breast cancer (OR=2.13, 95% CI=1.04-4.47, P < .05). And, the RAR beta 2 promoter hypermethylation was more common in the breast cancer patients of TNM III-IV stage than those patients of TNM I-II stage (OR=1.85, 95% CI=1.33-2.57, P < .05). In addition, the promoter hypermethylation of DARK, hMLH1, and p14 genes were significantly associated with the susceptibility of breast cancer (for DARK, OR=4.93, 95% CI=3.17-7.65; for hMLH1, OR=1.84, 95% CI=1.26-1.29; for p14, OR=22.52, 95% CI=7.00-72.41; for p15, OR=2.13, 95% CI=0.30-15.07).Conclusions: Our findings revealed that the RAR beta 2 promoter hypermethylation significantly increased the risk of breast cancer. In the meantime, the meta-analysis demonstrated that there were significant associations of RAR beta 2 promoter hypermethylation with lymph node metastasis and TNM-stage of breast cancer patients. In addition, DARK, hMLH1, and p14 genes promoter hypermethylation were significantly associated with the susceptibility of breast cancer.