RASSF1A promoter methylation was associated with the development, progression and metastasis of cervical carcinoma: a meta-analysis with trial sequential analysis.

Abstract

RASSF1A promoter methylation has been reported in cervical cancer. However, clinical effect of RASSF1A promoter methylation in cervical cancer remains unclear. This meta-analysis was conducted to assess the correlation between RASSF1A promoter methylation and cervical cancer and the association of RASSF1A promoter methylation with clinicopathological features. Electronic databases were searched to identify eligible publications. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Trial sequential analysis (TSA) was performed to assess the required study population information. Twenty-six papers published from 2001 to 2017 were analyzed in the meta-analysis, including a total of 1820 patients with cervical cancer, 507 patients with cervical intraepithelial neoplasia (CIN) lesions and 894 nonmalignant controls. RASSF1A promoter methylation was significantly increased in cervical cancer than in CIN lesions and nonmalignant tissue samples. In addition, RASSF1A promoter methylation was correlated with cervical cancer among two studies of blood and cytology samples (cancer vs nonmalignant controls). No correlation was found between RASSF1A promoter methylation and age factor, human papillomavirus (HPV) subtypes or clinical stage. RASSF1A promoter methylation was associated with tumor grade (grade 3-4 vs 1-2: OR 2.31, 95% CI 1.12-4.77, P=0.023), lymph node metastasis (yes vs no: OR 2.97, 95% CI 1.60-5.52, P=0.001), tumor histology (squamous cell carcinoma vs adenocarcinoma: OR 0.49, 95% CI 0.22-1.08, P=0.076), and HPV infection (positive vs negative: OR 0.45, 95% CI 0.28-0.73, P=0.001). TSA showed that the cumulative Z-curve did not cross the trial sequential monitoring boundary for significant results. RASSF1A promoter methylation may be associated with cervical cancer development, progression and metastasis. Methylated RASSF1A may be a noninvasive blood or cytology biomarker. Based on TSA, more studies are essential in the future.