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Open Access Research article

Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern China

Sheng Li Zhou1, Juan Cui2, Zong Min Fan1, Xue Min Li3, Ji Lin Li4, Bao Chi Liu5, Dong Yun Zhang1, Hong Yan Liu6, Xue Ke Zhao1, Xin Song1, Ran Wang1, Ze Chen Yan7, Hui Xing Yi1 and Li Dong Wang1*

Author Affiliations

1 Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China

2 Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China

3 Department of Pathology, Cixian Hospital, Cixian, Hebei 056500, China

4 Department of Pathology, Linzhou Esophageal Cancer Hospital, Linzhou, Henan 456500, China

5 Department of Surgery, Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai 201508, China

6 Henan Medical Genetics Institute, Henan People’s Hospital, Zhengzhou University, Zhengzhou, Henan 450003, China

7 Department of Urology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, China

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BMC Cancer 2013, 13:259  doi:10.1186/1471-2407-13-259

Published: 25 May 2013

Abstract

Background

The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. In this study, the polymorphism, promoter methylation and gene expression of RASSF1A were characterized in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA).

Methods

We firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay. Then, the promoter methylation status of the RASSF1A in ESCC (n=143), GCA (n=92) and corresponding adjacent normal tissues were further investigated using methylation-specific PCR (MSP) approach. Finally, the RASSF1A protein expression were determined in ESCC (n=27), GCA (n=24) and the matched adjacent normal tissues by immunohistochemical method.

Results

The frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02). Compared with Ala/Ala genotype, Ala/Se and Ser/Ser genotype significantly increased susceptibility to GCA (OR=2.06, 95% CI=1.09–3.97). However, this polymorphism had no association with ESCC (P=0.69). The promoter methylation of RASSF1A gene was significantly increased the risk to both ESCC (OR=5.90, 95% CI=2.78–12.52) and GCA (OR=7.50, 95% CI= 2.78–20.23). Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10–8.73; for differentiation: OR=0.29, 95% CI=0.12–0.69). RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03–0.83). In contrast, there was no statistical significance between RASSF1A positive expression and ESCC. The expression of RASSF1A protein trend to be positively related with older GCA patients (OR=16.20, 95% CI=1.57–167.74).

Conclusions

The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression. Whereas, RASSF1A hypermethylation may probably also be involved in esophageal squamous cell carcinogenesis.

Keywords:
Esophageal squamous cell carcinoma; Gastric cardia adenocarcinoma; A133S in RASSF1A; Polymorphism; Methylation; Protein expression