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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 8  |  Page : 292-295

The relationship between P16 gene promoter methylation and gastric cancer: A meta-analysis based on Chinese patients


1 Department of Medical Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022; First Department of Surgical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
2 Department of General Surgery, The Central Hospital of Lishui City, Lishui, Zhejiang 323000, China
3 Department of Medical Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China

Date of Web Publication17-Feb-2015

Correspondence Address:
Guoping Sun
Department of Medical Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.151535

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 > Abstract 

Objective: To evaluate the P16 gene promoter methylation rate in gastric cancer tissue and healthy controls. And further assess the clinical value of P16 gene promoter methylation as a biomarker for gastric cancer diagnosis.
Materials and Methods: Four databases, Medline, VIP, CNKI, WANFANG were searched to find the diagnostic trials about P16 gene promoter methylation in gastric cancer and healthy control. The pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR) and the receiver operating characteristic curve (ROC) were calculated by Meta-DiSc1.4 (http://www.hrc.es/investigacion/metadisc.html) software.
Results: Nine studies involving 487 gastric cancer patients and 271 healthy controls were included in this meta-analysis. The median methylation rate for gastric cancer group was 43.3% with its range of 28.3-64.4%. And the median methylation rate for healthy control group was 0.0% with its range of 0.0-13.3%. The methylation rate in gastric cancer was statistical higher than in the healthy control (P < 0.05). The pooled sensitivity, specificity, +LR, -LR and the area under the ROC curve were 0.44 (95% confidence interval [CI]: 0.40-0.49), 0.97 (95% CI: 0.95-0.99), 13.11 (95% CI: 4.02-42.63), 0.58 (95% CI: 0.49-0.70), 23.62 (95% CI: 6.90-80.90) and 0.44, respectively.
Conclusion: Our meta-analysis indicates that P16 gene promoter methylation array is a useful method for diagnosis of gastric cancer with relatively low sensitivity and very high specificity.

Keywords: Gastric cancer, P16 gene, methylation, meta-analysis


How to cite this article:
Peng D, Zhang H, Sun G. The relationship between P16 gene promoter methylation and gastric cancer: A meta-analysis based on Chinese patients. J Can Res Ther 2014;10, Suppl S4:292-5

How to cite this URL:
Peng D, Zhang H, Sun G. The relationship between P16 gene promoter methylation and gastric cancer: A meta-analysis based on Chinese patients. J Can Res Ther [serial online] 2014 [cited 2020 Oct 28];10:292-5. Available from: https://www.cancerjournal.net/text.asp?2014/10/8/292/151535


 > Introduction Top


DNA methylation is a biochemical process where a methyl group is added to the cytosine or adenine DNA nucleotides. [1] DNA methylation may stably alter the expression of genes in cells as cells divide and differentiate from embryonic stem cells into specific tissues. Recent studies showed that DNA methylation played an important role in the development of malignant carcinoma including the gastric cancer. And many studies indicated that tumor suppressor gene promoter methylation is an important mechanism for its tumorigenesis, which occur in the early stage of many types of carcinomas. [2] So, theoretically using methylation specific polymerase chain reaction (MSP) array detecting the methylation statues in tumor tissue or blood can be an important method for cancer detection.

Many articles reported the methylation rate in gastric cancer tissue and healthy gastric control tissue. The methylation rate in cancer tissue was generally higher than in the normal control gastric tissue, which indicated the methylation array could be a method for gastric cancer detection. Here, we conducted this meta-analysis to further evaluate the clinical value of P16 gene promoter methylation detection in the diagnosis of gastric cancer by meta-analysis.


 > Materials and methods Top


Search strategy

Four databases, Medline, VIP, CNKI, WANFANG were searched to find the diagnostic trials about P16 gene promoter methylation in gastric cancer and healthy control. The following search words were used: "Gastric cancer," "gastric carcinoma," "P16," "methylation." And the language was restriction to English and Chinese. The title and abstract of initial searched articles were assessed for appropriateness to the inclusion criteria. Then all potentially relevant studies were assessed in full-text paper and all references of included articles were further scanned for additional analysis.

Eligibility criteria

Clinical trials were included in this meta-analysis if they met the following criteria: (1) The study arrayed the methylation rate in gastric tissue of gastric cancer patients and healthy controls. (2) Studies evaluated the diagnosis value of P16 promoter methylation for gastric cancer. (3) Gastric cancer patients with pathology or cytology confirmed were diagnostic gold standard. (4) The exact number of true positive (tp), false positive (fp), false negative (fn) and true negative (tn) could be extracted from the original studies. (5) Studies that were published in full-text.

Data extraction

Two reviewers (Defeng Peng and Zhaojun Chen) independently reviewed and extracted the data from each included individual studies. If there was inconsistency, the original papers were retrieved and jointly investigated to resolve the disagreement. The following data and information were extracted for each study: (1) First author of the included studies. (2) Publication year; (3) Where the trails were done. (4) The gold diagnosis standard for gastric cancer. (5) The exact number of tp, fp, fn and tn for each study.

Statistical method

Meta-DiSc1.4 (http://www.hrc.es/investigacion/metadisc.html) was used to do the statistical analysis. The P16 gene promoter methylation rate was demonstrated by median with its range. The diagnosis index of sensitivity, specificity, positive likelihood ratio (+LR) negative likelihood ratio (−LR), and area under the receiver operating characteristic (ROC) were calculated according to random effect model or fixed effect model. The heterogeneity of the effect size across the included studies was evaluated statistically by the Chi-square.


 > Results Top


Study selection and characteristics

Nine studies involving 487 gastric cancer patients and 271 healthy controls were included in this meta-analysis. All of the data were based on Chinese gastric patients and controls. The median methylation rate for gastric cancer group was 43.3% with its range of 28.3-64.4%. And the median methylation rate for healthy control group was 0.0% with its range of 0.0-13.3%. The methylation rate in gastric cancer was statistical higher than in the healthy control (P < 0.05). The general characteristic of included trials is demonstrated in [Table 1].
Table 1: The general characteristic of included trials

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Sensitivity and specificity

We first evaluated the heterogeneity across the included nine studies. Statistical significant heterogeneity was observed in the aspects of sensitivity (I2 = 79.2%, P = 0.000) and specificity (I2 = 64.5%, P = 0.004). The diagnostic sensitivity and specificity were pooled by random effect model. And the pooled sensitivity and specificity were 0.44 (95% confidence interval [CI]: 0.40-0.49), 0.97 (95% CI: 0.95-0.99), respectively [Figure 1].
Figure 1: The forest plot of diagnostic sensitivity and specificity

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Positive likely hood ratio and negative likely hood ratio

With significant heterogeneity among the included studies (I2 = 59.5%, P = 0.011 for +LR, and I2 = 77.7%, P = 0.000 for −LR). So, we pooled the +LR and −LR by randomized effects model. The pooled diagnosis +LR and −LR were 13.11 (95% CI: 4.03-42.63), 0.5 8 (95% CI: 0.49-0.710), respectively [Figure 2].
Figure 2: The forest plot of the diagnostic positive likelihood ratio, negative likelihood ratio

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Diagnosis odds ratio

The diagnostic odds ratio was pooled by random effect model for its significant heterogeneity. The pooled diagnostic odds ratio was 23.62 (95% CI: 6.90-80.90) [Figure 3].
Figure 3: The forest plot of diagnostic odds ratio

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Area under the receiver operating characteristic curve

The area under the ROC curve was 0.47 (standard error [SE] = 0.29) with Q* = 0.45 (SE = 0.22), indicating a relative low level of diagnostic accuracy for P16 gene promoter methylation array [Figure 4].
Figure 4: The summary receiver operating characteristic curve for diagnosis by P16 gene promoter methylation

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 > Dicussion Top


Gastric cancer is rampant in many countries all over the world. In 2012, estimated 21,320 new cases of gastric cancer have been diagnosed, and 10,540 cased eventually die of this disease in the United States. [12] In China, gastric cancer is one of the leading causes of cancer-related death. But the exact incidence rate and modality rate were not reported for Chinese patients. As known, the gastric cancer was usually diagnosed at an advanced stage, which not suitable for surgery treatment with relative poor prognosis.

P16 (also known as cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor one and as several other synonyms), is a tumor suppressor gene that in humans is encoded by the CDKN2A gene. [13],[14] P16 plays an important role in cell cycle regulation by decelerating cells progression from G1 phase to S phase, and therefore acts as a tumor suppressor that is implicated in the prevention of cancers, notably melanoma, oropharyngeal squamous cell carcinoma, and gastric cancer. The CDKN2A gene is frequently mutated, deleted or promoter methylated in a wide variety of tumors including gastric carcinoma. Some articles showed that the P16 promoter methylation rate in gastric cancer tissue was higher than in healthy control gastric tissue. [2] But with a small number of cases and controls included in the original articles, the statistical power is limited. So, we performed this meta-analysis to further discuss the P16 gene promoter methylation rate in gastric cancer tissue and healthy gastric tissue.

In our study, nine clinical trials involving 487 gastric cancer patients and 271 healthy controls were included in this meta-analysis. The median methylation rate for gastric cancer group was 43.3% with its range of 28.3-64.4%. And the median methylation rate for healthy control group was 0.0% with its range of 0.0-13.3%. The methylation rate in gastric cancer was statistical higher than in the healthy control (P < 0.05). In most of the included studies, the methylation rate in healthy gastric tissue was zero. This result provided a pretty good opportunity for P16 gene promoter methylation array as a biomarker for gastric cancer diagnosis. We deem the P16 gene promoter methylation as the diagnostic test and then calculated the pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (−LR) and the area under the ROC curve. The results for the above index were 0.44 (95% CI: 0.40-0.49), 0.97 (95% CI: 0.95-0.99), 13.11 (95% CI: 4.02-42.63), 0.58 (95% CI: 0.49-0.70), 23.62 (95% CI: 6.90-80.90) and 0.44 respectively.

This study showed that P16 gene promoter methylation array is a useful method for differential diagnosis of gastric cancer with relatively low sensitivity and very high specificity.

But the total number of cases and controls were relative small in this meat-analysis. The heterogeneity for the effect size was significant. And all the patients included in the individual studies were restricted to Chinese.

 
 > References Top

1.
Iacobazzi V, Infantino V, Castegna A, Andria G. Hyperhomocysteinemia: Related genetic diseases and congenital defects, abnormal DNA methylation and newborn screening issues. Mol Genet Metab 2014;113:27-33.  Back to cited text no. 1
    
2.
Mikeska T, Craig JM. DNA methylation biomarkers: Cancer and beyond. Genes (Basel) 2014;5:821-64.  Back to cited text no. 2
    
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Liao AJ, Ling QH, Liu GX, Cao RX, Shi W. P16 exon1 promoter methylation in gastric cancer. Pract J Cancer 2001;16:284-7.  Back to cited text no. 3
    
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Shi W, Liao AJ, Liu Gx. Association between Helicobacter pylori Infection, p16 gene methylation and gastric cancer. Pract J Cancer 2001;16:400-2.  Back to cited text no. 4
    
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Yang YX, Kong XD, Zhang SZ. p16 and p15 gene expression and the methylation status abnoramalities of p16 and p15 gene promotor in gastric cancer. Basic Clin Med 2002;22:318-23.  Back to cited text no. 5
    
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Li SJ, Yuan H, Liu XY. The clinical study of the methylation in gene P16 in early diagnosis in stomach cancer. Chin J Misdiagnostics 2005;5:607-9.  Back to cited text no. 6
    
7.
Liu YH, Zhang LH, Ren H, Zhang GG, Qin F, Kong GZ, et al. Promoter hypermethylation of the p16 gene in pre- and post-gastrectomy plasma of patients with gastric adenocarcinoma. Beijing Da Xue Xue Bao 2005;37:257-60.  Back to cited text no. 7
    
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Liu WT, Jiao HL, Yang YL, Wang D, Zhang WM. P16 gene promoter hypermethylation in the development of gastric cancer. World Chin J Dig 2007;15:2839-43.  Back to cited text no. 8
    
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Li TC, Jiang DP, Lu LM, Zhao GH. p16 protein expression and promoter methylation of p16 gene in gastric cancer. J Pract Med 2007;23:3812-4.  Back to cited text no. 9
    
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Wei GH, Yang CY, Yang J, Li H, Gao ZA. Aberrant methylation of p16 gene in Gastric carcinoma and its precancerous lesions. Chin J Mod Med 2010;20:1490-3.  Back to cited text no. 10
    
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Ji J, Liu Y. The value of P16 gene promoter hypermethylation in development of gastric cancer. Contemp Med Forum 2014; 16:33-4.  Back to cited text no. 11
    
12.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.  Back to cited text no. 12
    
13.
Fizzotti M, Cimino G, Pisegna S, Alimena G, Quartarone C, Mandelli F, et al. Detection of homozygous deletions of the cyclin-dependent kinase 4 inhibitor (p16) gene in acute lymphoblastic leukemia and association with adverse prognostic features. Blood 1995;85:2685-90.  Back to cited text no. 13
    
14.
Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994;368:753-6.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

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