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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 8  |  Page : 287-291

The diagnostic value of DNA hypermethylation in stool for colorectal cancer: A meta-analysis


1 Department of Oncology Surgery, The First Affiliated Hospital of Bengbu Medical College, Anhui Province 233004, China
2 Department of Gastrointestinal Surgery, Guigang City People's Hospital, Guangxi Province 537100, China

Date of Web Publication17-Feb-2015

Correspondence Address:
Li-Yu Qian
Department of Oncology Surgery, The First Affiliated Hospital of Bengbu Medical College, Anhui Province 233004
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.151534

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 > Abstract 

Objective: We performed this meta-analysis to document the diagnostic performance of DNA hypermethylation in stool for colorectal cancer (CRC).
Materials and Methods: Relevant studies that reported the diagnostic performance of stool DNA hypermethylation in CRC and healthy control were searched and extracted from electronic databases. After careful evaluation of the included articles, the numbers of true positive, false positive, false negative and true negative cases identified by stool DNA hypermethylation were extracted and pooled for diagnostic sensitivity, specificity, positive likely hood ratio, negative likely hood ratio, diagnostic odds ratio and the summary receiver operating characteristic (SROC) curve. All the statistical analysis was done by MetaDiSc1.4 and STATA-11.0 software.
Results: Thirty diagnostic trails including 1,629 CRC patients and 1,531 controls were included in this meta-analysis according to the inclusion and exclusion criteria. The overall diagnostic value of DNA hypermethylation in stool for CRC was: Pooled sensitivity, 0.71 (0.69-0.73); pooled specificity, 0.92 (0.90-0.93); pooled positive likely hood ratio, 7.59 (5.83-9389); pooled negative likely hood ratio, 0.33 (0.27-0.42); pooled diagnostic odds ratio, 27.78 (19.94-38.72) and area under the SROC curve was 0.93 (0.91-0.95).
Conclusion: These results indicate a great diagnostic potential for DNA hypermethylation as a reliable marker in stool for CRC.

Keywords: Colorectal cancer, diagnosis, hypermethylation, meta-analysis, stool


How to cite this article:
Qian LY, Zhang W. The diagnostic value of DNA hypermethylation in stool for colorectal cancer: A meta-analysis. J Can Res Ther 2014;10, Suppl S4:287-91

How to cite this URL:
Qian LY, Zhang W. The diagnostic value of DNA hypermethylation in stool for colorectal cancer: A meta-analysis. J Can Res Ther [serial online] 2014 [cited 2020 Oct 28];10:287-91. Available from: https://www.cancerjournal.net/text.asp?2014/10/8/287/151534


 > Introduction Top


The NCCN colorectal cancer (CRC) screening guideline described various colorectal screening methods as well as recommended screening modalities such as colonoscopy, flexible sigmoidoscopy, double-contrast barium enema, computed tomographic colonography and fecal occult blood test. But none of them was ideal for their low sensitivity, low specificity or invasive. Recently, DNA aberrant hypermenthy in stool of colorectal patients were reported. Compared to healthy people the aberrant hypermenthy rate in CRC patients was always higher. Human DNA isolated from stool samples and analyzed for biomarkers that, in theory, could be useful for the early detection or screening of CRC. But the diagnostic performance by detection, DNA aberrant hypermethylation was inconclusive. So, we made this meta-analysis to further clarify the clinical value of DNA methylation array in stool for diagnostic of CRC.


 > Materials and methods Top


Search

The PubMed, Web of Science and China National Knowledge Infrastructure databases were systematically searched using the terms "CRC" or "colon cancer" or "rectal cancer" or "colorectal carcinoma" or "colon carcinoma" or "rectal carcinoma" or "colorectal neoplasm" or "colon neoplasm" or "rectal neoplasm" and "stool" and "methylation" or "hypermethylation". All the search procedures were done by two reviewers independently. We also reviewed citations of the original included studies in order to find other studies that meet the requirements of this meta-analysis. When necessary, we contacted the correspondence author of the studies for additional information.

Data extraction

Two authors (Li-Yu Qian and Wei Zhang) independently read the full text papers and extracted the data using a standardized data extraction sheet. Discrepancies were resolved by discussion and consensus. The following information and diagnostic were extracted carefully in each of the included papers. (1) General information: First author and the correspondence author; year of publication; where the study was performed; stool diabetic autonomic neuropathy methylation detection methods; (2) data for pooled analysis: Diagnostic sensitivity, specificity; true positive; false positive; false negative; true negative.

Quantitative data synthesis and analysis

The pooled sensitivity, specificity, positive likely hood ratio, negative likely hood ratio, diagnostic odds ratio, area under the receiver operating characteristic (ROC) cure and their 95% confidence interval were calculated by STATA-11.0 software (Stata Corporation, College Station, TX). A random-effects synthesis model was used for significant heterogeneity otherwise fixed effect synthesis model was purchased. Statistical heterogeneity among the included studies was assessed by I 2 statistic. Forest plots were constructed to show the effect size of all the studies and the variability of the pooled estimates. Funnel plot and Egger's line regression analysis were used to detect the publication bias.


 > Results Top


Eligible studies

Thirty trails involving 1,629 CRC patients and 1,531 controls were recruited in this meta-analysis according to the inclusion and exclusion criteria. The average sample size of the included studies was 105 with its range of 25-545. Twelve studies come from China, six trails from United States, three articles from Holland and nine studies from other countries. The median DNA methylation rate was 66.2% with its range of 20.0-96.1% in the CRC group and 26.5% with its range of 8.0-61.5% in the control group. [Table 1] summarizes the baseline characteristics of the included studies.
Table 1: Characteristics of the included 30 studies

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Meta-analysis

We first evaluated the diagnostic sensitivity and specificity heterogeneity among the included 30 studies. The heterogeneity was significant in both diagnostic sensitivity (I2 = 89.9%, P = 0.00) and specificity (I2 = 50.0, P = 0.00). So, the pooled results of diagnostic sensitivity and specificity were calculated by random effects model with its pooled diagnostic sensitivity of 0.71 (0.69-0.73), [Figure 1] and pooled diagnostic specificity of 0.92 (0.90-0.93), [Figure 2]. For the positive and negative likely hood ratio, significant heterogeneity also existed among the included studies, the pooled positive and negative likely hood ratio were 7.59 (5.83-9389), [Figure 3] and 0.33 (0.27-0.42), [Figure 4], respectively. The diagnostic odds ratio was also pooled by random effect mode for its significant heterogeneity (I2 = 36.7, P = 0.02). And the pooled diagnostic odds ratio was 27.78 (19.94-38.72), [Figure 5]. We further calculate the summary ROC (SROC) curve by sensitivity versus 1-specificity. The area under the ROC curve was 0.93 (0.91-0.95) [Figure 6].
Figure 1: The forest plot of diagnostic sensitivity of DNA hypermethylation in stool for colorectal cancer

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Figure 2: The forest plot of diagnostic specificity of DNA hypermethylation in stool for colorectal cancer

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Figure 3: The forest plot of diagnostic + LR of DNA hypermethylation in stool for colorectal cancer

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Figure 4: The forest plot of diagnostic − LR of DNA hypermethylation in stool for colorectal cancer

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Figure 5: The forest plot of diagnostic odds ratio of DNA hypermethylation in stool for colorectal cancer

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Figure 6: Summary receiver operating characteristic plot with best-fitting asymmetric curve of DNA hypermethylation in stool for colorectal cancer diagnosis

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Publication bias

The funnel plot of publication bias was synthesized by diagnostic odds ratio versus effective sample size. No publication bias of this meta-analysis was found (t = −0.12, P = 0.91), [Figure 7].
Figure 7: Funnel plot of publication bias of DNA hypermethylation in stool for colorectal cancer diagnosis

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 > Discussion Top


Colorectal cancer is one of the most common malignancies worldwide. In the year of 2012, about 103,170 new cases of colon cancer and 40,290 new cases of rectal cancer have been diagnosed in the USA. [31] In China, CRC incidence and mortality have increased rapidly during the past two decades, making it the fifth leading cause of cancer-related death. [32] Generally, colorectal patients with early stage disease (stage I localized disease) treated with surgery have a 5-years survival rate of 96%. [33] But the prognosis of patients with advanced CRC was relatively poor. Thus, the key point for improving the prognosis of CRC was to screen the high-risk population for CRC.

Various studies reported that the aberrant DNA hypermethylation in stool of colorectal patients were found. And in a healthy population, this phenomenon was rarely found. So, this provided a theoretical method for screening or diagnosis of CRC. But the published articles about using DNA methylation array in stool for screening or diagnosis of CRC was varied a lot with a wide range of sensitivity and specificity. Kang et al.[4] use methylation-specific PCR array to detect the MAL, CDKN2A and MGMT genes promoter methylation as a biomarker in stool for CRC. In that study, they included 69 patients with CRC and 26 healthy controls. The methylation rate in colorectal patients was much higher than in the healthy controls indicating that stool DNA methylation may serve as a noninvasive approach for the screening of CRC and pre-malignant lesions.

In this meta-analysis, we finally included 1,629 CRC patients and 1,531 controls with 30 diagnostic clinical studies. The overall diagnostic value of DNA hypermethylation in stool for CRC was: Pooled sensitivity, 0.71 (0.69-0.73); pooled specificity, 0.92 (0.90-0.93); pooled positive likely hood ratio, 7.59 (5.83-9389); pooled negative likely hood ratio, 0.33 (0.27-0.42); pooled diagnostic odds ratio, 27.78 (19.94-38.72) and area under the SROC curve was 0.93 (0.91-0.95). In the past few years, numerous hypermethylated genes isolated from stool samples have been utilized as biomarkers for the screening or detection of CRC, including APC, INK4A, RARβ, MGMT and Chen et al. [26] And the diagnostic sensitivities and specificities reported in these articles were highly variable. In our meta-analysis, we calculated the summary sensitivity and specificity by pooled the individual data. The pooled results showed that the diagnostic sensitivity was moderate, but the specificity was pretty high. So, these results indicate a great diagnostic potential for DNA hypermethylation as a reliable marker in stool for CRC.

 
 > References Top

1.
Xiao ZJ, Wang XY, Li BS, Li Z, Ma QY, Zhu WS, et al. Colorectal cancer screening by detecting the methylation status of vimentin and SFRP2. Mod Dig Interv 2014; 4:13-6, 20.  Back to cited text no. 1
    
2.
Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, et al. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 2012;142:248-56.  Back to cited text no. 2
    
3.
Xu MH, Cai KY, Tu Y. Value of fecal DNA methylation analysis in early diagnosis of colorectal cancer. Chin J Clin Gastroenterol 2012;24:17-9.  Back to cited text no. 3
    
4.
Kang YP, Cao FA, Chang WJ, Lou Z, Wang H, Wu LL, et al. Gene methylation in stool for the screening of colorectal cancer and pre-malignant lesions. Zhonghua Wei Chang Wai Ke Za Zhi 2011;14:52-6.  Back to cited text no. 4
    
5.
Zhang JP, Wang J, Gui YL, Zhu QQ, Xu ZW, Li JS. Human stool vimentin, oncostatin M receptor and tissue factor pathway inhibitor 2 gene methylation analysis for the detection of colorectal neoplasms. Zhonghua Yi Xue Za Zhi 2011;91:2482-4.  Back to cited text no. 5
    
6.
Ahlquist DA, Taylor WR, Mahoney DW, Zou H, Domanico M, Thibodeau SN, et al. The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia. Clin Gastroenterol Hepatol 2012;10:272-7.e1.  Back to cited text no. 6
    
7.
Bosch LJ, Oort FA, Neerincx M, Khalid-de Bakker CA, Terhaar sive Droste JS, Melotte V, et al. DNA methylation of phosphatase and actin regulator 3 detects colorectal cancer in stool and complements FIT. Cancer Prev Res (Phila) 2012;5:464-72.  Back to cited text no. 7
    
8.
Azuara D, Rodriguez-Moranta F, de Oca J, Soriano-Izquierdo A, Mora J, Guardiola J, et al. Novel methylation panel for the early detection of colorectal tumors in stool DNA. Clin Colorectal Cancer 2010;9:168-76.  Back to cited text no. 8
    
9.
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.  Back to cited text no. 9
    
10.
Baek YH, Chang E, Kim YJ, Kim BK, Sohn JH, Park DI. Stool methylation-specific polymerase chain reaction assay for the detection of colorectal neoplasia in Korean patients. Dis Colon Rectum 2009;52:1452-9.  Back to cited text no. 10
    
11.
Li M, Chen WD, Papadopoulos N, Goodman SN, Bjerregaard NC, Laurberg S, et al. Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol 2009;27:858-63.  Back to cited text no. 11
    
12.
Melotte V, Lentjes MH, van den Bosch SM, Hellebrekers DM, de Hoon JP, Wouters KA, et al. N-Myc downstream-regulated gene 4 (NDRG4): A candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst 2009;101:916-27.  Back to cited text no. 12
    
13.
Hellebrekers DM, Lentjes MH, van den Bosch SM, Melotte V, Wouters KA, Daenen KL, et al. GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer. Clin Cancer Res 2009;15:3990-7.  Back to cited text no. 13
    
14.
Mayor R, Casadomé L, Azuara D, Moreno V, Clark SJ, Capellà G, et al. Long-range epigenetic silencing at 2q14.2 affects most human colorectal cancers and may have application as a non-invasive biomarker of disease. Br J Cancer 2009;100:1534-9.  Back to cited text no. 14
    
15.
Kim MS, Louwagie J, Carvalho B, Terhaar Sive Droste JS, Park HL, Chae YK, et al. Promoter DNA methylation of oncostatin m receptor-beta as a novel diagnostic and therapeutic marker in colon cancer. PLoS One 2009;4:e6555.  Back to cited text no. 15
    
16.
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.  Back to cited text no. 16
    
17.
Glöckner SC, Dhir M, Yi JM, McGarvey KE, Van Neste L, Louwagie J, et al. Methylation of TFPI2 in stool DNA: A potential novel biomarker for the detection of colorectal cancer. Cancer Res 2009;69:4691-9.  Back to cited text no. 17
    
18.
Wang DR, Tang D. Hypermethylated SFRP2 gene in fecal DNA is a high potential biomarker for colorectal cancer noninvasive screening. World J Gastroenterol 2008;14:524-31.  Back to cited text no. 18
    
19.
Itzkowitz S, Brand R, Jandorf L, Durkee K, Millholland J, Rabeneck L, et al. A simplified, noninvasive stool DNA test for colorectal cancer detection. Am J Gastroenterol 2008;103:2862-70.  Back to cited text no. 19
    
20.
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.  Back to cited text no. 20
    
21.
Itzkowitz SH, Jandorf L, Brand R, Rabeneck L, Schroy PC 3 rd , Sontag S, et al. Improved fecal DNA test for colorectal cancer screening. Clin Gastroenterol Hepatol 2007;5:111-7.  Back to cited text no. 21
    
22.
Abbaszadegan MR, Tavasoli A, Velayati A, Sima HR, Vosooghinia H, Farzadnia M, et al. Stool-based DNA testing, a new noninvasive method for colorectal cancer screening, the first report from Iran. World J Gastroenterol 2007;13:1528-33.  Back to cited text no. 22
    
23.
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.  Back to cited text no. 23
    
24.
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.  Back to cited text no. 24
    
25.
Lenhard K, Bommer GT, Asutay S, Schauer R, Brabletz T, Göke B, et al. Analysis of promoter methylation in stool: A novel method for the detection of colorectal cancer. Clin Gastroenterol Hepatol 2005;3:142-9.  Back to cited text no. 25
    
26.
Chen WD, Han ZJ, Skoletsky J, Olson J, Sah J, Myeroff L, et al. Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst 2005;97:1124-32.  Back to cited text no. 26
    
27.
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.  Back to cited text no. 27
    
28.
Fu L, Sheng JQ, Meng XM, Meng MM, Jin P, Li AQ, et al. The early diagnosis significance of detecting Vimentin gene methylation from patients′ fecal DNA in colorectal cancer. Chin J Gastroenterol Hepatol 2010;19:601-3.  Back to cited text no. 28
    
29.
Ling ZA, Chen LS, He CG. The significance of p16 methylation analysis is in stool in early diagnosis of colorectal cancer. J Colorectal Anal Surg 2009;15:144-8.  Back to cited text no. 29
    
30.
Huang ZH, Li LH, Yang F, Liu ZH, Hu Y, Song MX, et al. Stool DNA methylation analysis in the diagnosis of colorectal cancer. Chin J Lab Med 2007;30:617-20.  Back to cited text no. 30
    
31.
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014;64:104-17.  Back to cited text no. 31
    
32.
Sung JJ, Lau JY, Goh KL, Leung WK, Asia Pacific Working Group on Colorectal Cancer. Increasing incidence of colorectal cancer in Asia: Implications for screening. Lancet Oncol 2005;6:871-6.  Back to cited text no. 32
    
33.
Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart AK. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol 2010;28:264-71.  Back to cited text no. 33
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
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