Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma
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Cancer Cell International Open Access
PRIMARY RESEARCH
Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma Gang Xu†, Xiaoxiang Zhou†, Jiali Xing†, Yao Xiao, Bao Jin, Lejia Sun, Huayu Yang, Shunda Du, Haifeng Xu* and Yilei Mao*
Abstract Background: RAS association domain family protein 1A (RASSF1A) promoter hypermethylation is suggested to be linked to hepatocellular carcinoma (HCC), but the results remained controversial. Methods: We evaluated how RASSF1A promoter hypermethylation affects HCC risk and its clinicopathological characteristics through meta-analysis. Data on DNA methylation in HCC and relevant clinical data were also collected based on The Cancer Genome Atlas (TCGA) database to investigate the prognostic role of RASSF1A promoter hypermethylation in HCC. Results: Forty-four articles involving 4777 individuals were enrolled in the pooled analyses. The RASSF1A promoter methylation rate was notably higher in the HCC cases than the non-tumor cases and healthy individuals, and was significantly related to hepatitis B virus (HBV) infection-positivity and large tumor size. Kaplan–Meier survival analysis revealed that HCC cases with RASSF1A promoter hypermethylation had worse outcomes. Receiver operating characteristic curves confirmed that RASSF1A promoter methylation may be a marker of HCC-related prognoses. Conclusions: RASSF1A promoter hypermethylation is a promising biomarker for the diagnosis of HCC from tissue and peripheral blood, and is an emerging therapeutic target against HCC. Keywords: RASSF1A promoter hypermethylation, Hepatocellular carcinoma, Biomarker, Overall survival, Diagnosis Introduction Liver cancer (LC) is the sixth leading cause of cancerrelated morbidity, and the fourth major cause of cancerrelated death, worldwide. Approximately 841,000 newly diagnosed LC cases and 782,000 LC-related deaths are reported annually [1]. Hepatocellular carcinoma (HCC) is a major histological subtype of LC, accounting for 70% to 85% of all LC cases, globally [2]. While significant progress has been made in the diagnosis and treatment *Correspondence: [email protected]; pumch‑[email protected] † Gang Xu Xiaoxiang Zhou and Jiali Xing contributed equally to the work Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing 100730, China
HCC, patients with the disease still have unsatisfactory prognoses [3]. Consequently, new clinical strategies are needed to improve the efficacy of HCC treatment, including the development of novel diagnostic and prognostic biomarkers. Recent emerging evidence suggests that the accumulation of epigenetic and genetic alterations has a role in the different stages of liver carcinogenesis [4]. Besides, CpG island methylation within gene promoters, key epigenetic regulatory factors, has an important role in HCC initiation and development [5]. Promoter hypermethylation may result in the silencing of some tumor suppressors that regulate the cell signaling pat
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