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

BMC Cancer

Sheng Li Zhou³  Juan Cui⁷  Zong Min Fan³  Xue Min Li¹  Ji Lin Li⁵  Bao Chi Liu⁴  Dong Yun Zhang³  Hong Yan Liu⁶  Xue Ke Zhao³  Xin Song³  Ran Wang³  Ze Chen Yan²  Hui Xing Yi³  Li Dong Wang³ 

[1] Department of Pathology, Cixian Hospital, Cixian, Hebei 056500, China

[2] Department of Urology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, China

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

[4] Department of Surgery, Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai 201508, China

[5] Department of Pathology, Linzhou Esophageal Cancer Hospital, Linzhou, Henan 456500, China

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

[7] Cancer Research Center, Xinxiang Medical University, Xinxiang, Henan 453003, China

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

Others  :  1079732
DOI  :  10.1186/1471-2407-13-259

 received in 2013-01-01, accepted in 2013-05-21,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Zhou et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Ke L: Mortality and incidence trends from esophagus cancer in selected geographic areas of China circa 1970–90. Int J Cancer 2002, 102:271-274.
• [3]Sun XB, Liu ZC, Liu SZ, Li BY, Dai DX, Quan PL: Descriptive analysis of incidence and time trends of esophageal and gastic cancers in Linzhou city. Zhouhua Zhong Liu Za Zhi 2007, 29:764-767.
• [4]Sun G, Wang S, Hu X, Su J, Huang T, Yu J: Fumonisin B1 contamination of home-grown corn in high-risk areas for esophageal and liver cancer in China. Food Addit Contam 2007, 24:181-185.
• [5]Guohong Z, Min S, Duenmei W, Songnian H, Min L, Jinsong L: Genetic heterogeneity of oesophageal cancer in high-incidence areas of southern and northern China. PLoS One 2010, 5:e9668.
• [6]Wang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y: Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat Genet 2010, 42:759-763.
• [7]Máthé E: RASSF1A, the new guardian of mitosis. Nat Genet 2004, 36:117-118.
• [8]Agathanggelou A, Cooper WN, Latif F: Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res 2005, 65:3497-3508.
• [9]Li B, Wang B, Niu LJ, Jiang L, Qiu CC: Hypermethylation of multiple tumor-related genes associated with DNMT3b up-regulation served as a biomarker for early diagnosis of esophageal squamous cell carcinoma. Epigenetics 2011, 6:307-316.
• [10]Cong DG, Wang SF: Hypermethylation of promoter region of RAS association domain family gene1A in esophageal squamous cell carcinoma and significance thereof. Zhonghua Yi Xue Za Zhi 2007, 87:2932-2934.
• [11]Kanzaki H, Hanafusa H, Yamamoto H, Yasuda Y, Imai K, Yano M: Single nucleotide polymorphism at codon 133 of the RASSF1 gene is preferentially associated with human lung adenocarcinoma risk. Cancer Lett 2006, 238:128-134.
• [12]Schagdarsurengin U, Seidel C, Ulbrich EJ, Kölbl H, Dittmer J, Dammann R: A polymorphism at codon 133 of the tumor suppressor RASSF1A is associated with tumorous alteration of the breast. Int J Oncol 2005, 27:185-191.
• [13]Siewert JR, Hölscher AH, Becker K, Gössner W: Cardia cancer: attempt at a therapeutically relevant classification. Chirurg 1987, 58:25-32.
• [14]Tran GD, Sun XD, Abnet CC, Fan JH, Dawsey SM, Dong ZW: Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int J Cancer 2005, 113:456-463.
• [15]Greene FL: AJCC cancer staging manual. New York: Springer Verlag; 2002.
• [16]Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 1996, 93:9821-9826.
• [17]Wang LD, Hong JY, Qiu SL, Gao H, Yang CS: Accumulation of p53 protein in human esophageal precancerous lesions: a possible early biomarker for carcinogenesis. Cancer Res 1993, 53:1783-1787.
• [18]Kim YT, Park JY, Jeon YK, Park SJ, Song JY, Kang CH: Aberrant promoter CpG island hypermethylation of the adenomatosis polyposis coli gene can serve as a good prognostic factor by affecting lymph node metastasis in squamous cell carcinoma of the esophagus. Dis Esophagus 2009, 22:143-150.
• [19]Yamaguchi S, Kato H, Miyazaki T, Sohda M, Kimura H, Ide M: RASSF1A gene promoter methylation in esophageal cancer specimens. Dis Esophagus 2005, 18:253-256.
• [20]Wong ML, Tao Q, Fu L, Wong KY, Qiu GH, Law FB: Aberrant promoter hypermethylation and silencing of the critical 3p21 tumour suppressor gene, RASSF1A, in Chinese oesophageal squamous cell carcinoma. Int J Oncol 2006, 28:767-773.
• [21]Guo W, Dong Z, Chen Z, Yang Z, Wen D, Kuang G: Aberrant CpG island hypermethylation of RASSF1A in gastric cardia adenocarcinoma. Cancer Invest 2009, 27:459-465.