|Year : 2014 | Volume
| Issue : 7 | Page : 225-228
Tumor M2-pyruvate kinase in stool as a biomarker for diagnosis of colorectal cancer: A meta-analysis
Jin-Xi Huang1, Yi Zhou2, Cheng-Hu Wang3, Wei-Wei Yuan3, Zhan-dong Zhang3, Xie-Fu Zhang4
1 Department of General Surgery, First Affiliated Hospital of Zhengzhou University, Henan Zhengzhou 450052; Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Zhengzhou 450003, China
2 Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Zhengzhou 450003, China
3 Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Zhengzhou 450003, China
4 Department of General Surgery, First Affiliated Hospital of Zhengzhou University, Henan Zhengzhou 450052, China
|Date of Web Publication||29-Nov-2014|
Department of General Surgery, First Affiliated Hospital of Zhengzhou University, Henan Zhengzhou 450052
Source of Support: None, Conflict of Interest: None
Objective: The aim of this meta-analysis was to evaluate the diagnosis value of tumor M2-pyruvate kinase (M2-PK) in stool as a biomarker for diagnosis of colorectal cancer.
Materials and Methods: By searching the databases of Cochrane Library, PubMed, China national knowledge Information and Wanfang, the diagnosis study related to tumor M2-PK in stool as a biomarker for diagnosis of colorectal cancer were screened and included in this study. The pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (−LR) and the receiver operating characteristic curve (ROC) were calculated by stata 11.0 software.
Results: According to the including criteria, 14 trials including 1990 subjects were finally included in this meta-analysis. The pooled diagnosis sensitivity, specificity, +LR, −LR and area under curve were 0.78 (95% confidence interval [CI]: 0.74-0.81), 0.77 (95% CI: 0.76-0.79), 4.38 (95% CI: 3.27-5.88), 0.28 (95% CI: 0.23-0.34) and 0.86 (95% CI: 0.834-0.89). No statistical publication bias was found in this study.
Conclusion: Tumor M2-PK in stool can be a useful biomarker in the diagnosis of colorectal cancer with relative high sensitivity and specificity.
Keywords: Biomarker, colorectal cancer, diagnosis, meta-analysis, tumor M2-pyruvate kinase
|How to cite this article:|
Huang JX, Zhou Y, Wang CH, Yuan WW, Zhang Zd, Zhang XF. Tumor M2-pyruvate kinase in stool as a biomarker for diagnosis of colorectal cancer: A meta-analysis. J Can Res Ther 2014;10, Suppl S3:225-8
|How to cite this URL:|
Huang JX, Zhou Y, Wang CH, Yuan WW, Zhang Zd, Zhang XF. Tumor M2-pyruvate kinase in stool as a biomarker for diagnosis of colorectal cancer: A meta-analysis. J Can Res Ther [serial online] 2014 [cited 2019 Oct 16];10:225-8. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/225/145886
| > Introduction|| |
In the past several decades, although several colorectal cancer screen projects with colonoscopy had been completed, the overall high cost rendered them to be in effective in controlling colorectal cancer on a global scale.  Thus, to develop an alternative modality based on blood biomarkers as the first-line screening test is an alternative ideal way. Tumor M2-pyruvate kinase (M2-PK), a tumor-associated dimeric form of enzyme pyruvate kinase, is commonly elevated in colorectal cancer. Several studies have found that it is always over expression in the stool of patients with colorectal cancer. , However, the clinical diagnosis value of M2-PK in stool was not consistent with each individual study. Hence, we perform this meta-analysis based on published trials to evaluate the clinical value of tumor M2-PK in stool as a biomarker for diagnosis of colorectal cancer by pooling the sensitivity and specificity.
| > Materials and methods|| |
0 Literature searching
Prospective diagnosis trials related to evaluating the diagnosis value of tumor M2-PK in stool as a biomarker for diagnosis of colorectal cancer were searched in the Cochrane Library, PubMed, China national knowledge Information and Wanfang databases. The following search words were used: "Colorectal cancer," "colorectal carcinoma," "colon cancer," "rectal cancer," "tumor M2-pyruvate," "M2-PK." And the language was restriction to English and Chinese.
Clinical trials were included in this meta-analysis if they met the following criteria: (1) The study design was prospective; (2) studies were about the diagnosis value of M2-PK in stool as a biomarker for diagnosis of colorectal cancer; (3) subjects in the case group were diagnosed by gold standard, such as pathology or cytology; (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.
Data of each individual study were extracted independently by two investigators (Huang Jinxi and WANG Chenghu) and cross-checked to reach a consensus. The following data and information were extracted for each study: (1) First and corresponding author of the study; (2) country of patients included; (3) year of publication; (4) the gold diagnosis method for colorectal cancer patients; (5) the exact number of TP, FP, FN and TN for each individual study.
All the analyses were undertaken by Meta-DiS1.4 (Ramo'n y Cajal Hospital, Madrid, Spain) and STATA 12.0 (Stata Corporation, College Station, TX). The diagnosis index of sensitivity, specificity, positive likelihood ratio (+LR) negative likelihood ratio (−LR), and area under the receiver operating characteristic curve (ROC) were pooled by the statistical software. The heterogeneity of the effect size across the included studies was evaluated by the Chi-square.
| > Results|| |
0 The general characteristic of included studies
Finally, 14 trials evaluating the tumor M2-PK in stool as a biomarker for diagnosis of colorectal cancer were finally included in this meta-analysis. ,,,,,,,,,,,,, There were 679 subjects in the case group and 1311 subjects in the controls group. Of the included 14 trials, 6 articles were published in Chinese, and other 8 were published in English. The year of publication range from 2004 to 2012. The general characteristic of the 14 included studies was demonstrated in [Table 1].
The diagnosis sensitivity and specificity
The significant heterogeneity was found in the effect size of sensitivity (χ2 = 24.16, P = 0.029) and specificity (χ2 = 84.11, P = 0.000) across the included studies. Thus, the randomized effects model was used to calculate the pooled sensitivity and specificity. Moreover, the pooled sensitivity and specificity were 0.78 (95% confidence interval [CI]: 0.74-0.81), 0.77 (95% CI: 0.76-0.79) respectively [Figure 1].
|Figure 1: The forest plot of pooled diagnosis sensitivity and specificity|
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The diagnosis positive likelihood ratio and negative likelihood ratio
Obvious heterogeneity across the included trials was found. Hence, randomized effected model was used for pooled analysis. The combined diagnosis + LR and − LR were 4.38 (95% CI: 3.27-5.88), 0.28 (95% CI: 0.23-0.34), respectively [Figure 2].
|Figure 2: The forest plot of pooled diagnosis positive likelihood ratio and negative likelihood ratio|
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The area under the receiver operating characteristic curve
The diagnosis area under the ROC was calculated according to the Bayes theorem. The area under the ROC was 0.86 with its 95% CI of 0.83-0.9 [Figure 3].
|Figure 3: The area under the receiver operating characteristic curve for diagnosis of diagnosis of colorectal cancer|
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The publication bias was evaluated by line regression method. And no statistical publication was observed in this study with a P = 0.169 [Figure 4].
| > Discussion|| |
About 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008 worldwide.  Cancer has become the major cause of death of the human being. Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, with over 1.2 million new cancer cases and 608,700 deaths estimated to have occurred in 2008.  It is estimated that as global communities become more developed and the world population ages, the morbidity and mortality rates due to colorectal cancer will increase substantially. 
Effective colorectal screening can detect the early stage patients and a significant decrease the motility of colorectal patients. Recently, the main colorectal screen methods were fecal occult blood test (FOBT) and colonoscopy. But each of them has its own drawbacks. For FOBT, it is a non-invasive, inexpensive and easily applicable screening test which patients can readily perform in the comfort of their own home. However, the positive results could be affected by other bow bleeding diseases such as stomach ulcer, biliary tract bleeding and et al. So, the diagnosis specificity for this test was relatively low. For colonoscopy, the benefit of colonoscopy is that it allows for a full structural examination of the colon and rectum in a single session and for the detection of colorectal polyps and cancers accompanied by biopsy or polypectomy. But the disadvantages of colonoscopy are obvious with invasive and discomfortable. Therefore, the serum biomarker for screening colorectal cancer with relative high sensitivity specificity and non or mini invasive is ideal.
Pyruvate kinase plays an important role in the glycolytic pathway. One of its functions is to control nucleotide triphosphate generation.  Different isoforms of this enzyme exist (pyruvate kinases L, R, M1, M2, Tumor M2), which are tissue-specifically expressed in various organisms. Many studies have demonstrated M2-PK was over expressed in several solid tumors such as gastric cancer, colorectal cancer and et al. So, it is also called tumor M2-PK. Recently, clinical trials have demonstrated that the M2-PK could also be detected in the serum and stool by an ELISA based two monoclonal antibodies. , And the elevated level of M2-PK was also found in patients with solid tumors such as colorectal carcinoma. Hence, it could be the biomarker for diagnosis of colorectal cancer. But the diagnosis value of M2-PK for diagnosis of colorectal cancer was not consistent with each individual studies. In order to further evaluation the clinical value of M2-PK as a biomarker for colorectal cancer, we perform this meta-analysis with published articles.
In this meta-analysis, 14 trials including 1990 subjects were finally included. The pooled diagnosis sensitivity and specificity were 0.78 and 0.77 with significant heterogeneity among the trials which indicated that the average missed diagnosis rate and false diagnosis were 0.78 and 0.77 respectively. With a single biomarker, the results were acceptable. And the pooled + LR, −LR and area under curve (AUC) were 4.38 (95% CI: 3.27-5.88), 0.28 (95% CI: 0.23-0.34) and 0.86 (95% CI: 0.834-0.89). The AUC-ROC reflects the relationship between sensitivity and specificity for a given test. High-quality tests will have an AUC-ROC approaching 1. In this meta-analysis, area under the summary receiver operating characteristic curve were 0.86 (95% CI: 0.834-0.89) which indicated the diagnosis value of stool M2-PK was relative high.
Although this meta-analysis indicated tumor M2-PK in stool can be a useful biomarker in diagnosis of colorectal cancer with relative sensitivity and specificity, there are still several drawbacks in this study: (1) Relative small subjects number in each individual study; (2) significant heterogeneity among the included trials; (3) language restriction; (4) and different control population type.
| > References|| |
Rossini LG, Ribeiro PA, Rodrigues FC, Filippi SS, Zago Rde R, Schneider NC, et al.
Transrectal ultrasound - Techniques and outcomes in the management of intestinal endometriosis. Endosc Ultrasound 2012;1:23-35.
Shastri YM, Loitsch S, Hoepffner N, Povse N, Hanisch E, Rösch W, et al.
Comparison of an established simple office-based immunological FOBT with fecal tumor pyruvate kinase type M2 (M2-PK) for colorectal cancer screening: Prospective multicenter study. Am J Gastroenterol 2008;103:1496-504.
Chen L, He Y, Wu Y, Wang D, Wang Q. Expression and clinical significance of tumor M2 pyruvate kinase in colorectal cancer pa-tients. Chin J Health Lab Technol 2008;18:1830-1.
Parente F, Marino B, Ilardo A, Fracasso P, Zullo A, Hassan C, et al.
A combination of faecal tests for the detection of colon cancer: A new strategy for an appropriate selection of referrals to colonoscopy? A prospective multicentre Italian study. Eur J Gastroenterol Hepatol 2012;24:1145-52.
Zhang Y, Wang L, Guo JZ. The value of tumor M2 pyruvate kinase in diagnosis of colon cancer. Jiangsu Med J 2011;37:523-5.
Li Y, Wang JJ. Clinical significance of blood and fecal tumor M2-pyruvate kinase expression in patients with colorectal cancer. Nan Fang Yi Ke Da Xue Xue Bao 2011;31:2087-9.
Koss K, Maxton D, Jankowski JA. Faecal dimeric M2 pyruvate kinase in colorectal cancer and polyps correlates with tumour staging and surgical intervention. Colorectal Dis 2008;10:244-8.
Zhang YG, Lin RZ. Significance of fecal tumor m2 pyruvate kinase for detection of gastrointestinal cancers. Chin J Gastroenterol 2007;12:465-8.
Haug U, Rothenbacher D, Wente MN, Seiler CM, Stegmaier C, Brenner H. Tumour M2-PK as a stool marker for colorectal cancer: Comparative analysis in a large sample of unselected older adults vs colorectal cancer patients. Br J Cancer 2007;96:1329-34.
Zhang JC, Wang G. Value of fecal tumor M2 pyruvate kinase in diagnosis of colorectal cancer. World Chine J Digestology 2007;15:193-6.
Mulder SA, van Leerdam ME, van Vuuren AJ, Francke J, van Toorenenbergen AW, Kuipers EJ, et al.
Tumor pyruvate kinase isoenzyme type M2 and immunochemical fecal occult blood test: Performance in screening for colorectal cancer. Eur J Gastroenterol Hepatol 2007;19:878-82.
Tonus C, Neupert G, Sellinger M. Colorectal cancer screening by non-invasive metabolic biomarker fecal tumor M2-PK. World J Gastroenterol 2006;12:7007-11.
Guan-Fu WJ, Yi-Hua LP, Xin-Min S. Evaluation of fecal tumor m2 pyruvate kinase combined with fecal occult blood test as a detecting tool for colorectal cancer. J Sun Yat Sen Univ (Med Sci) 2006;27:350-3.
Hardt PD, Mazurek S, Toepler M, Schlierbach P, Bretzel RG, Eigenbrodt E, et al.
Faecal tumour M2 pyruvate kinase: A new, sensitive screening tool for colorectal cancer. Br J Cancer 2004;91:980-4.
Naumann M, Schaum B, Oremek GM, Hanisch E, Rosch W, Mossner J, et al
. Faecal pyruvate kinase type M2--a valid screening parameter for colorectal cancer? Preliminary results from a multicenter comparative study. Dtsch Med Wochenschr (1946) 2004;129:1806-7.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.
Mazurek S, Grimm H, Boschek CB, Vaupel P, Eigenbrodt E. Pyruvate kinase type M2: A crossroad in the tumor metabolome. Br J Nutr 2002;87 Suppl 1:S23-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]