|Year : 2016 | Volume
| Issue : 5 | Page : 30-33
Diagnostic value of secreted frizzled-related protein 2 gene promoter hypermethylation in stool for colorectal cancer: A meta-analysis
Zhiran Zhou, Huitian Zhang, Yunxia Lei
Department of Gastroenterology, Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Xinjiang 830000, P.R. China
|Date of Web Publication||7-Oct-2016|
Department of Gastroenterology, Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Xinjiang 830000
Source of Support: None, Conflict of Interest: None
Objective: To evaluate the diagnostic value of secreted frizzled-related protein 2 (SFRP2) gene promoter hypermethylation in stool for colorectal cancer (CRC).
Materials and Methods: Open published diagnostic study of SFRP2 gene promoter hypermethylation in stool for CRC detection was electronic searched in the databases of PubMed, EMBASE, Cochrane Library, Web of Science, and China National Knowledge Infrastructure. The data of true positive, false positive false negative, and true negative identified by stool SFRP2 gene hypermethylation was extracted and pooled for diagnostic sensitivity, specificity, and summary receiver operating characteristic (SROC) curve.
Results: According to the inclusion and exclusion criteria, we finally included nine publications with 792 cases in the meta-analysis. Thus, the diagnostic sensitivity was aggregated through random effect model. The pooled sensitivity was 0.82 with the corresponding 95% confidence interval (95% CI) of 0.79–0.85; the pooled specificity and its corresponding 95% CI were 0.47 and 0.40–0.53 by the random effect model; we pooled the SROC curve by sensitivity versus specificity according to data published in the nine studies. The area under the SROC curve was 0.70 (95% CI: 0.65–0.73).
Conclusion: SFRP2 gene promoter hypermethylation in stool can was a potential biomarker for CRC diagnosis with relative high sensitivity.
Keywords: Colorectal cancer, hypermethylation, meta-analysis, secreted frizzled-related protein 2 gene, stool
|How to cite this article:|
Zhou Z, Zhang H, Lei Y. Diagnostic value of secreted frizzled-related protein 2 gene promoter hypermethylation in stool for colorectal cancer: A meta-analysis. J Can Res Ther 2016;12, Suppl S1:30-3
|How to cite this URL:|
Zhou Z, Zhang H, Lei Y. Diagnostic value of secreted frizzled-related protein 2 gene promoter hypermethylation in stool for colorectal cancer: A meta-analysis. J Can Res Ther [serial online] 2016 [cited 2021 Sep 26];12:30-3. Available from: https://www.cancerjournal.net/text.asp?2016/12/5/30/191625
| > Introduction|| |
Secreted frizzled-related protein 2 (SFRP2) gene encodes a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of frizzled proteins. SFRPs act as soluble modulators of Wnt signaling., The previous studies show that the promoter region of this gene was hypermethylated in colorectal cancer (CRC)., Hence, hypermethylation of SFRP2 gene is a potential marker for the presence of CRC. However, diagnostic sensitivity and specificity for hypermethylation of SFRP2 gene as a biomarker was not in accordance with each other. Thus, we performed this meta-analysis to further evaluate the diagnostic sensitivity and specificity of FRP2 gene promoter hypermethylation in stool for CRC.
| > Materials and Methods|| |
Open published diagnostic study of SFRP2 gene promoter hypermethylation in stool for CRC detection was electronic searched in the databases of PubMed, EMBASE, Cochrane Library, Web of Science, and China National Knowledge Infrastructure. The searching words are “CRC/colon cancer/rectal cancer/colorectal carcinoma/colon carcinoma/rectal carcinoma/colorectal neoplasm/colon neoplasm/rectal neoplasm” and “stool,” “methylation/hypermethylation” and “frizzled-related protein 2/SFRP2.” The references of included studies were also manually searched to retrieve additional studies. The search procedure was done by Zhou Zhiran and Jin Jin independently.
The data and general information for each of the included studies were extracted by Zhou Zhiran and Jin Jin independently then checked by the third reviewer Lei Yunxia. The extracted data and information included the first author, the year of publication, the cases of true positive, false positive false negative and true negative detected by SFRP2 gene promoter hypermethylation in stool.
The statistical analysis was done by MetaDiSc1.4 (http://www.biomedsearch.com/nih/Meta-DiSc-software-meta- analysis/16836745.html) and Stata 11.0 software (http://www.stata.com; Stata Corporation, College Station, TX, USA). Chi-square test was used to calculate the statistical heterogeneity. Fixed or random effect model was used to pooled the sensitivity and specificity according to the heterogeneity. The publication bias was evaluated by funnel plot and Egger's line regression test.
| > Results|| |
General information for the included studies
According to the inclusion and exclusion criteria, we finally included nine publications with 792 cases in the meta-analysis. Six studies use methylation-specific polymerase chain reaction method to detect the methylation of SFRP2 gene promoter region; two studies use methylight and 1 use combined bisulfite restriction analysis method. Five studies made in China mainland, one in Hongkong, one in Japan, one in Germany, and one in Australia. The general characteristics of the included nine publications were shown in [Table 1].
We first assess the heterogeneity for the included nine studies by Chi-square test. We found that significant heterogeneity among the publications for the diagnostic sensitivity (P < 0.05). Thus, the diagnostic sensitivity was aggregated through random effect model. The pooled sensitivity was 0.82 with the corresponding 95% confidence interval (95% CI) of 0.79–0.85 [Figure 1].
|Figure 1: The diagnosis sensitivity of secreted frizzled-related protein 2 gene promoter hypermethylation in stool for colorectal cancer|
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Statistical heterogeneity was also found in the aspect of specificity. The pooled specificity and its corresponding 95% CI were 0.47 and 0.40–0.53 by the random effect model [Figure 2].
|Figure 2: The diagnosis specificity of secreted frizzled-related protein 2 gene promoter hypermethylation in stool for colorectal cancer|
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Area under the receiver operating characteristic curve
We pooled the summary receiver operating characteristic (SROC) curve by sensitivity versus specificity according data published in the nine studies. The area under the SROC curve was 0.70 (95% CI: 0.65–0.73) [Figure 3].
|Figure 3: Receiver operating characteristic curve of secreted frizzled-related protein 2 gene promoter hypermethylation in stool for colorectal cancer|
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The publication bias was evaluated by funnel plot which was synthesized by diagnostic odds ratio versus 1/square root effective sample size. And no publication bias of this meta-analysis was found (t = −1.40, P = 0.21) [Figure 4].
| > Discussion|| |
CRC is one of the most diagnosed carcinomas in human beings with the incidence of more than 100,000 in the year of 2012. With the development of China's economic, people's lifestyle has been changed with more calories intake and less labor. Thereafter, the morbidity of colorectal has increased rapidly during the past two decades, making it the fifth leading cause of cancer-related death. The prognosis is relative well in patients with early stage. However, the prognosis of CRC patients with the advanced metastasis diseases was relative poor with low 5 years survival rate. Hence, the early diagnosis for CRC is important for the well prognosis.
The National Comprehensive Cancer Network CRC guideline described several colorectal early diagnosis methods as well as recommended screening modalities such as colonoscopy, flexible sigmoidoscopy, double-contrast barium enema, computed tomographic colonography, and fecal occult blood test. Recently, researchers have focus on the DNA hypermethylation in stool as a biomarker for colorectal diagnosis. Previously published studies demonstrated that the promoter region of tumor suppressor gene was usually hypermethylated in most of the malignant tumors compared to normal tissue or subjects without malignant disease.,,, Theoretically, promoter region hypermethylation of tumor suppressor gene can be used as potential biomarker for cancer diagnosis. Hypermethylation of SFRP2 gene in promoter region has been reported by several open published studies. However, the number of cases included in each studies was relative small with small statistical power. In our meta-analysis, we pooled data published in nine studies and found that the diagnostic sensitivity of SFRP2 gene promoter hypermethylation in stool for CRC was relative high which indicated that SFRP2 gene promoter hypermethylation can be used as an important method for CRC screening. However, the pooled specificity was 0.47 which indicated the false positive was relative high according to SFRP2 gene promoter hypermethylation for colorectal diagnosis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Pohl S, Scott R, Arfuso F, Perumal V, Dharmarajan A. Secreted frizzled-related protein 4 and its implications in cancer and apoptosis. Tumour Biol 2015;36:143-52.
Bergmann K, Sypniewska G. Secreted frizzled-related protein 4 (SFRP4) and fractalkine (CX3CL1) – Potential new biomarkers for ß-cell dysfunction and diabetes. Clin Biochem 2014;47:529-32.
Zhang W, Bauer M, Croner RS, Pelz JO, Lodygin D, Hermeking H, et al.
DNA stool test for colorectal cancer: Hypermethylation of the secreted frizzled-related protein-1 gene. Dis Colon Rectum 2007;50:1618-26.
Leung WK, To KF, Man EP, Chan MW, Hui AJ, Ng SS, et al.
Detection of hypermethylated DNA or cyclooxygenase-2 messenger RNA in fecal samples of patients with colorectal cancer or polyps. Am J Gastroenterol 2007;102:1070-6.
Tang D, Liu J, Wang DR, Yu HF, Li YK, Zhang JQ. Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer. Clin Invest Med 2011;34:E88-95.
Nagasaka T, Tanaka N, Cullings HM, Sun DS, Sasamoto H, Uchida T, et al.
Analysis of fecal DNA methylation to detect gastrointestinal neoplasia. J Natl Cancer Inst 2009;101:1244-58.
Wang DR, Tang D. Hypermethylated SFRP2 gene in fecal DNA is a high potential biomarker for colorectal cancer screening. World J Gastroenterol 2008;14:524-31.
Huang ZH, Li LH, Yang F, Wang JF. Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions. World J Gastroenterol 2007;13:950-4.
Müller HM, Oberwalder M, Fiegl H, Morandell M, Goebel G, Zitt M, et al.
Methylation changes in faecal DNA: A marker for colorectal cancer screening? Lancet 2004;363:1283-5.
Meihua X, Kegen C, Ying T. The diagnostic value of DAN methylationin stool for colorectal cancer. Chin J Clin Gastroenterol 2012;12:17-9.
Zhaohui H, Lihua L, Fan Y, Zhijun L, Yu H, Mingxu S, et al
. The clincial value of detection DNA methylation in stool for colorectal patients. Chin J Lab Med 2007;27:617-20.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29.
Yee YK, Tan VP, Chan P, Hung IF, Pang R, Wong BC. Epidemiology of colorectal cancer in Asia. J Gastroenterol Hepatol 2009;24:1810-6.
Zhang J, Dai WJ, Yang XZ. Methylation status of TRAF2 is associated with the diagnosis and prognosis of gastric cancer. Int J Clin Exp Pathol 2015;8:14228-34.
Guo T, Ren Y, Wang B, Huang Y, Jia S, Tang W, et al.
Promoter methylation of BRCA1 is associated with estrogen, progesterone and human epidermal growth factor receptor-negative tumors and the prognosis of breast cancer: A meta-analysis. Mol Clin Oncol 2015;3:1353-60.
Konecny M, Markus J, Waczulikova I, Dolesova L, Kozlova R, Repiska V, et al.
The value of SHOX2 methylation test in peripheral blood samples used for the differential diagnosis of lung cancer and other lung disorders. Neoplasma 2016;63:246-53.
Ramachandran K, Speer C, Nathanson L, Claros M, Singal R. Role of DNA methylation in cabazitaxel resistance in prostate cancer. Anticancer Res 2016;36:161-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]