title: Decreased expression and frequent promoter hypermethylation of RASSF2 and RASSF6 correlate with malignant progression and poor prognosis of gastric cardia adenocarcinoma.
abstract: The RAS-association domain family (RASSF) consists of 10 members, and several members act as tumor suppressor genes and epigenetically inactivated in different tumor types. The present study investigated the role and methylation status of RASSF2, RASSF3, RASSF4, and RASSF6 in the pathogenesis and prognosis of GCA. Quantitative real-time RT-PCR, Western blot, and immunohistochemistry (IHC) methods were used respectively to detect the expression of RASSF2, RASSF3, RASSF4, and RASSF6 in 135 GCA cases and BS-MSP method was used to clarify the methylation status of these four genes. Decreased mRNA and protein expression of RASSF2, RASSF3, RASSF4, and RASSF6 were detected in GCA tumor tissues. Aberrant CpG island methylation of RASSF2, RASSF4, and RASSF6 were detected in GCA tumor tissues and were inversely correlated with the expression levels of these genes. Both of RASSF2 and RASSF6 expression and methylation were associated with TNM stage, depth of invasion, LN metastasis, distant metastasis or recurrence, and UGIC family history. GCA patients with simultaneous negative protein expression of RASSF2 and RASSF6 or with simultaneous methylation of both genes demonstrated poor patient survival. These results suggest that down-regulation of RASSF2, RASSF3, RASSF4, and RASSF6 is a tumor-specific phenomenon and the inactivation of RASSF2 and RASSF6 may be associated with tumor progression. Inactivation of RASSF2, RASSF4, and RASSF6 through CpG island methylation may play important roles in GCA carcinogenesis. A combination of RASSF2 and RASSF6 expression or hypermethylation may serve as useful prognostic biomarker for GCA. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. dongzhiming2000@163.com.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Supeng
authors.initials: S
authors.lastname: Shen
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Kuang
authors.affiliation: Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins; D002299:Cardia / Q000473:pathology*; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C425300:RASSF2 protein, human; C519911:RASSF6 protein, human; D025521:Tumor Suppressor Proteins; D020559:Monomeric GTP-Binding Proteins
keywords: RASSF; expression; gastric cardia adenocarcinoma; methylation