|Year : 2014 | Volume
| Issue : 8 | Page : 310-313
A systematic review and meta-analysis of runt-related transcription factor 3 gene promoter hypermethylation and risk of gastric cancer
Yongxin Xia, Meng Zhang, Xiangdong Zhang, Xiaozheng Liu
Department of Gastroenterolog, Nanyang City Center Hospital, Nanyang 473009, China
|Date of Web Publication||17-Feb-2015|
Department of Gastroenterolog, Nanyang City Center Hospital, Nanyang, Henan Province
Source of Support: None, Conflict of Interest: None
Objective: To evaluate the association between runt-related transcription factor 3 (RUNX3) gene promoter hypermethylation and gastric cancer risk by meta-analysis.
Materials and Methods: By searching Medline, EMBASE, Ovid, China National Knowledge Infrastructure and Wanfang databases, the open published articles reporting the relationship between RUNX3 gene promoter hypermethylation, and gastric carcinoma risk, were screened. The aggregated odds ratio of RUNX3 gene promoter hypermethylation in cancerous sample of gastric cancer patients compared to normal gastric tissue of gastric cancer patients was pooled by statistic software STATA-11.0.
Results: Sixteen studies include 2631 samples were finally included in this meta-analysis. The aggregated results indicated that the hypermethylation rate in cancerous tissue was much higher than that in normal tissue (55.1% vs. 26.5%, P < 0.05). And the pooled results showed that the RUNX3 gene promoter methylation odds in tumor tissue in gastric cancer patients compared to normal gastric tissue was 5.47 (95% confidence interval: 3.34-8.96).
Conclusion: RUNX3 gene promoter hypermethylation rate was much higher in tumor tissue than that in normal gastric tissue in the patient with gastric cancer.
Keywords: Gastric cancer, hypermethylation, meta-analysis, runt-related transcription factor gene 3
|How to cite this article:|
Xia Y, Zhang M, Zhang X, Liu X. A systematic review and meta-analysis of runt-related transcription factor 3 gene promoter hypermethylation and risk of gastric cancer. J Can Res Ther 2014;10, Suppl S4:310-3
|How to cite this URL:|
Xia Y, Zhang M, Zhang X, Liu X. A systematic review and meta-analysis of runt-related transcription factor 3 gene promoter hypermethylation and risk of gastric cancer. J Can Res Ther [serial online] 2014 [cited 2020 Oct 28];10:310-3. Available from: https://www.cancerjournal.net/text.asp?2014/10/8/310/151539
| > Introduction|| |
Gastric cancer is one of the most happened malignant carcinoma in many countries in the world. In China, the crude mortality rate of gastric cancer was 25.2/100,000 (32.8/100,000 in men and 17.0/100,000 in women), which accounted for 23.2% of the total cancer deaths in 1990-1992, making gastric cancer the first leading cause of cancer death in that period of time.  But no exact incidence rate of gastric cancer in China was reported currently.
Recently, CpG island hypermethylation of tumor suppressor gene was found to be important for carcinogenesis in gastric cancer. Runt-related transcription factor 3 (RUNX3) is a member of the runt domain family of transcription factors, also known as polyomavirus enhancer-binding protein 2 (PEBP2)/core binding factors (CBF).  And several studies reported that the promoter of the RUNX3 was usually hypermethylated in gastric patients. But with small number cases included in each study, the statistical power is limited. So, we performed this meta-analysis to further evaluated that whether the hypermethylation rate between tumor tissue and normal gastric tissue was different or not.
| > Materials and methods|| |
The screening procedure of the relevant studies was showed in [Figure 1]. The published articles reporting the RUNX3 promoter hypermethylation in patients with gastric cancer were searched in the databases of Pubmed, EMBASE, China National Knowledge Infrastructure and Wanfan. "Gastric cancer", "gastric carcinoma", "stomach cancer", "stomach carcinoma" and "RUNX3 OR AML2 OR CBFA3 OR PEBP" were used as the MeSH and free text word when searching the databases.
The methylation was detected by methylation-specific PCR (MSP) or quantitative MSP (q-MSP); the methylation rate in the cancer tissue and autologous controls would be drawn in the original studies included in this meta-analysis. All potentially relevant articles were assessed in full-text paper, and all references of included articles were scanned for additional analysis according to the Cochrane handbook for systematic review. 
The odds ratio (OR) with 95% confidence intervals (CI) of RUNX3 promoter hypermethylation in cancer tissue compared to relative normal tissue for the included studies was pooled by STATA/SE-11.0 (http://www.stata.com; Stata Corporation, College Station, TX) statistic software. Statistical heterogeneity among the included articles was evaluated by I 2 .Without significant heterogeneity (I 2 = 50%), the fixed-effect method was used to pool the data. Inversely, random-effect method (Dersimonian-Laird method) was taken to pool the OR.
| > Results|| |
General characteristics of included studies
By searching the databases, 16 clinical studies were included in this meta-analysis. Six studies come from Japan, six articles from China, two from South Korea and two from other countries. The hypermethylation rate in tumor tissue ranges from 24.3% to 95.6% in cancer tissue and 2.7% to 95.6% in relative normal tissue. The detailed information was showed in [Table 1].
Pooled results of this meta-analysis
The aggregate results indicated that the median hypermethylation rate in cancerous tissue was much higher than that in normal tissue (55.1% vs. 26.5%, P < 0.05). And the pooled results showed that the RUNX3 gene promoter methylation odds in tumor tissue in gastric cancer patients compared to normal gastric tissue was 5.47 (95% CI: 3.34-8.96) [Figure 2].
|Figure 2: Forest plot of pooled odds ratio for runt-related transcription factor-3 gene promoter methylation in cancer tissue versus normal gastric tissue|
Click here to view
The hypermethylation rate in tumor tissue ranges from 24.3% to 95.6% with a meidan of 55.0% in cancer tissue and 2.7% to 95.6% with a median of 12.9% in normal gastric tissue. The hypermethylation rate in cancer tissue was significant higher than that in normal gastric tissue (P < 0.05) [Figure 3].
|Figure 3: Hypermethylation rate in gastric cancer tissue and normal gastric tissue|
Click here to view
A funnel plot of methylation status of gastric cancer tissue versus normal tissue showed that two studies exceeded the 95% confidence limits [Figure 4]. So, the publication bias may be existed in this meta-analysis.
| > Discussion|| |
DNA hymethylation is a biochemical process involving the addition of a methyl group to thecytosine or adenine DNA nucleotides.  DNA hymethylation may affect the transcription of the tumor suppressor genes in two ways. Firstly, the methylated DNA may physically impede the binding of transcriptional proteins to the gene itself.  Secondly, may be with more important, methylated DNA may be bound by proteins known as methyl-CpG-binding domain proteins.
Runt-related transcription factor 3 gene encodes a member of the runt domain-containing family of transcription factors. A heterodimer of this protein and a beta subunit forms a complex that binds to the core DNA sequence 5'-YGYGGT-3' found in a number of enhancers and promoters,  and can either activate or suppress transcription. RUXN3 functions as a tumor suppressor and the gene is frequently deleted or transcriptionally silenced in gastric cancer. As reported, one of the mechanism of RUNX3 genes silence was associated with its promoter CpG island hypermethylation.  And in the previous studies, hypermethylated promoter of RUNX3 in gastric cancer was reported. But with small number cases included in each individual article, different methylation array and different race, the methylation rate for RUNX3 was ranged a lot from each other. And whether the hypermethylation rate was the same or not in the gastric cancer tissue and normal gastric tissue was not clear. So, we searched the databases and included all the articles reporting the RUNX3 gene promoter methylation in gastric cancer.
In this meta-analysis, we found that 16 studies include 2631 samples were suitable for inclusion. The aggregated results indicated that the hypermethylation rate in cancerous tissue was much higher than that in normal tissue (55.1% vs. 26.5%, P < 0.05). This indicated that the RUNX3 gene promother hypermethylation may play an important role in the development of gastric carcinoma. And the pooled results showed that RUNX3 gene promoter methylation odds in tumor tissue in gastric cancer patients compared to normal gastric tissue was 5.47 (95% CI: 3.34-8.96). These results demonstrated that the hypermethylation rate in gastric cancer tissue was 5.47 times higher than that in normal gastric tissue.
Inclusion, this meta-analysis showed RUNX3 gene promoter hypermethylation rate was much higher in tumor tissue than that in normal gastric tissue in the patient with gastric cancer. But the conclusion should be further evaluated for its obvious publication bias.
| > References|| |
Yang L. Incidence and mortality of gastric cancer in China. World J Gastroenterol 2006;12:17-20.
Li QL, Ito K, Sakakura C, Fukamachi H, Inoue Ki, Chi XZ, et al.
Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 2002;109:113-24.
Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley and Sons; 2008. Available from: http://www.cochrane-handbook.org/
. [Last accessed on 2011 Dec 12; Last updated on 2011 Mar 20].
Waki T, Tamura G, Sato M, Terashima M, Nishizuka S, Motoyama T. Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neoplastic gastric epithelia. Cancer Sci 2003;94:360-4.
Nakase Y, Sakakura C, Miyagawa K, Kin S, Fukuda K, Yanagisawa A, et al.
Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography. Br J Cancer 2005;92:562-9.
Homma N, Tamura G, Honda T, Matsumoto Y, Nishizuka S, Kawata S, et al.
Spreading of methylation within RUNX3 CpG island in gastric cancer. Cancer Sci 2006;97:51-6.
So K, Tamura G, Honda T, Homma N, Endoh M, Togawa N, et al.
Quantitative assessment of RUNX3 methylation in neoplastic and non-neoplastic gastric epithelia using a DNA microarray. Pathol Int 2006;56:571-5.
Gargano G, Calcara D, Corsale S, Agnese V, Intrivici C, Fulfaro F, et al.
Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell′Italia Meridionale) prospective study. Ann Oncol 2007;18 Suppl 6:vi103-9.
Li LY, Li JK, Shen Y, Yu L, Zhang JH. Promoter methylation and expression of Runx3 gene in gastric cancer. Zhonghua Wei Chang Wai Ke Za Zhi 2008;11:379-82.
Kitajima Y, Ohtaka K, Mitsuno M, Tanaka M, Sato S, Nakafusa Y, et al. Helicobacter pylori
infection is an independent risk factor for Runx3 methylation in gastric cancer. Oncol Rep 2008;19:197-202.
Song HJ, Shim KN, Joo YH, Kim SE, Jung SA, Yoo K. Methylation of the Tumor Suppressor Gene RUNX3 in Human Gastric Carcinoma. Gut Liver 2008;2:119-25.
Kim JH, Jung EJ, Lee HS, Kim MA, Kim WH. Comparative analysis of DNA methylation between primary and metastatic gastric carcinoma. Oncol Rep 2009;21:1251-9.
Chen W, Gao N, Shen Y, Cen JN. Hypermethylation downregulates Runx3 gene expression and its restoration suppresses gastric epithelial cell growth by inducing p27 and caspase3 in human gastric cancer. J Gastroenterol Hepatol 2010;25:823-31.
Hiraki M, Kitajima Y, Sato S, Mitsuno M, Koga Y, Nakamura J, et al.
Aberrant gene methylation in the lymph nodes provides a possible marker for diagnosing micrometastasis in gastric cancer. Ann Surg Oncol 2010;17:1177-86.
Lin H, Cao J, Zhang B, Wu YM, Zou XP. Correlations of RUNX3 and RASSF1A promoter hypermethylation with the progression and metastasis of gastric carcinoma. World Chin J Digestol 2010;18:889-96.
Hu SL, Huang DB, Sun YB, Wu L, Xu WP, Yin S, et al.
Pathobiologic implications of methylation and expression status of Runx3 and CHFR genes in gastric cancer. Med Oncol 2011;28:447-54.
Mikata R, Fukai K, Imazeki F, Arai M, Fujiwara K, Yonemitsu Y, et al.
BCL2L10 is frequently silenced by promoter hypermethylation in gastric cancer. Oncol Rep 2010;23:1701-8.
Tang GH, Sun SW, He XS. Correlation of CpG methylation status of Runx3 with pathogenesis of gastric carcinoma. Zhonghua Bing Li Xue Za Zhi 2012;41:314-9.
He XB, Zhang HY. The clincal significance of Runx3 gene promother methylation in gastric cancer. Jilin Med J 2012;33:227-8.
Hua F, Fang N, Li X, Zhu S, Zhang W, Gu J. A meta-analysis of the relationship between RARß gene promoter methylation and non-small cell lung cancer. PLoS One 2014;9:e96163.
Choy MK, Movassagh M, Goh HG, Bennett MR, Down TA, Foo RS. Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated. BMC Genomics 2010;11:519.
Levanon D, Eisenstein M, Groner Y. Site-directed mutagenesis supports a three-dimensional model of the runt domain. J Mol Biol 1998;277:509-12.
Fuks F. DNA methylation and histone modifications: Teaming up to silence genes. Curr Opin Genet Dev 2005;15:490-5.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]