|Year : 2014 | Volume
| Issue : 8 | Page : 287-291
The diagnostic value of DNA hypermethylation in stool for colorectal cancer: A meta-analysis
Li-Yu Qian1, Wei Zhang2
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 Publication||17-Feb-2015|
Department of Oncology Surgery, The First Affiliated Hospital of Bengbu Medical College, Anhui Province 233004
Source of Support: None, Conflict of Interest: None
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
| > Introduction|| |
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|| |
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.
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|| |
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.
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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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|| |
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.  In China, CRC incidence and mortality have increased rapidly during the past two decades, making it the fifth leading cause of cancer-related death.  Generally, colorectal patients with early stage disease (stage I localized disease) treated with surgery have a 5-years survival rate of 96%.  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. 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.  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.
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