Promoter hypermethylation of RARβ2, 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 RARβ2, 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 RARβ2, 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 RARβ2, DAPK, hMLH1, p14, and p15 promoter hypermethylation with breast cancer pathogenesis. Trial sequential analysis (TSA) was applied to observe the reliability of pooled results of RARβ2 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 RARβ2 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 RARβ2 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 RARβ2 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 DAPK, hMLH1, and p14 genes were significantly associated with the susceptibility of breast cancer (for DAPK, 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 RARβ2 promoter hypermethylation significantly increased the risk of breast cancer. In the meantime, the meta-analysis demonstrated that there were significant associations of RARβ2 promoter hypermethylation with lymph node metastasis and TNM-stage of breast cancer patients. In addition, DAPK, hMLH1, and p14 genes promoter hypermethylation were significantly associated with the susceptibility of breast cancer.