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. 2020 Feb 25;12(5):440–450. doi: 10.3892/mco.2020.2002

A meta-analysis of serological thymidine kinase 1 as a marker for colorectal benign and malignant tumor risk assessment

Li Dang *, Hongbo Ma *, Ailian Hei 1, Shuai Xu 1, Ji Zhou 1, Ellen He 1, Sven Skog 1,✉
PMCID: PMC7087469  PMID: 32257201

Abstract

The present study investigated whether a concentration of serum thymidine kinase 1 (STK1p) could be used to distinguish between healthy individuals, patients with colorectal benign tumors and individuals with colorectal cancer (CRC). The effectiveness of surgery on patients with CRC was monitored. A total of 20 publications containing patients with CRC (n=1,836), patients with colorectal benign tumors (n=774) and healthy controls (n=1,701) were analysed in the present meta-analysis. The publications were collected from PubMed, Embase, CENTRAL, CNKI, Wanfang, VIP and SinoMed databases from January 1, 2009 until August 31, 2019. Articles were analyzed according to sensitivity (Forest plot) and publication bias (Begg's plot, Egger's linear regression) using fixed or random effect models to calculate the weighted mean difference. Study quality was checked using the Newcastle-Ottawa Scale Document Quality Assessment Scale. The meta-analysis followed the PRISMA statement. The results revealed that STK1p significantly distinguished healthy individuals and those with colorectal benign tumors from patients with CRC, and from patients with benign tumors (P<0.000001). STK1p levels also decreased by 40% following surgery (P<0.0001), which corresponded to half-life of ~1 month. The quality of the present study was high and no bias was identified among publication. It was concluded that STK1p was a reliable biomarker for the early detection of benign lesions, which may therefore prevent their future development into colorectal malignancies. STK1p may also be used for the clinical dynamic monitoring of the effectiveness of surgery in patients with CRC. Combining STK1p with colorectal-associated biomarkers, in addition to the determination of tumor stage and grade may therefore be of use.

Keywords: thymidine kinase 1, serum thymidine kinase 1 concentration, colorectal cancer, neoplastic colorectal polyp (colorectal benign tumor), meta-analysis

Introduction

According to the World Health Organization, the number of newly diagnosed colorectal cancer (CRC) cases will increase by 77% and the number of deaths by 80% by 2030 (1,2). The expected increase in CRC will mainly occur in less developed countries,due to the development of a lifestyle closed to Western countries (3-5).

The neoplastic transformation time of CRC is ~10-15 years (6-9), and the 5 year survival following treatment 50-60% (10,11). Reliable diagnostic, prognostic and predictive biomarkers are required (12). At present, the most accepted tests for CRC are fecal occult blood test, colonoscopy and sigmoidoscopy (13). Tumor node metastasis (TNM) staging and carcinoembryonic antigen level are also used. However, most of these tests have been reported to be too insensitive for accurate individual prognosis (14,15). Tumor biomarkers with a high sensitivity and specificity are required. In this meta-analysis, the use of serum thymidine kinase 1 (STK1p) concentration for prognosis and treatment monitoring in CRC patients is discussed.

STK1p has been proven useful for predicting recurrence and survival in many types of human cancer (16,17). TK1 is a kinase enzyme that converts deoxythymidine to deoxythymidine monophosphate and is involved in the synthesis of DNA, and thus related to cell growth rate (proliferation). The new-generation STK1p concentration assay shows an area under the curve (AUC) value of 0.96(18), and is a more reliable assay than the serum TK activity (19,20) and serum TK1 sandwich ELISA (21) assays. Low STK1p values are associated with a better prognosis (16,18,22-27). The STK1p marker is an independent prognostic factor for survival in CRC patients (n=504) (28). STK1p can distinguish malignant patients from benign tumor patients and healthy individuals, as well as predict the prognosis of survival and relapse. STK1p can also monitor the effect of the treatment, and is a useful biomarker for predicting the development of malignancies and discovering early-stage tumors (18,26,28).

A number of studies have focused on the use of STK1p in colorectal benign and malignant tumor patients, but most of them included a limited number of cases, thus reducing the reliability of the conclusions. Therefore, 20 colorectal studies were collected for the present meta-analysis, in order to obtain a sufficient number of cases. The results showed that STK1p values are significantly higher in CRC patients, as compared to heathy individuals or patients with benign tumors. STK1p was also used to monitor the effect of the surgery.

Materials and methods

Literature search

A systematic literature search was conducted through the PubMed, Embase, CENTRAL, CNKI, Wanfang, VIP and SinoMed databases until August 31, 2019, using the following strategy keywords: (‘thymidine kinase 1’ or ‘TK1’) and (‘colorectal’ or ‘colon’ or ‘rectal’ or ‘colorectum’ or ‘rectum’) and (‘cancer’ or ‘tumor’ or ‘carcinoma’ or ‘malignancy’). A more detailed description of the search strategy used is described in the beginning of the Results section. The literature search was restricted to human studies. There were no language restrictions.

The meta-analysis followed the PRISMA guidelines. The quality of the meta-analysis as a study was investigated using the Newcastle-Ottawa Scale Document Quality Assessment Scale (NOS). Only studies using the STK1p assay developed by us, tested in many clinical studies and statistically proved to be reliable were selected (summary in refs. 27,28), in order to guarantee the high quality of the STK1p results. Since no specific review protocol suitable for our meta-analysis was found, our own protocol was used.

All analyses were based on previously published studies, and therefore no ethical approval and patient consent were required.

Inclusion and exclusion criteria Inclusion criteria

i) STK1p as an endpoint; ii) STK1p was measured by the kit developed by SSTK Ltd; iii) patients with adenomatous polyps were identified by clinical endoscopy and pathological diagnosis. Patients were identified by pathological diagnosis, classified as stage I-III and grade 1-3, and confirmed to have no residual tumor following surgery; iv) healthy individuals were used as the control group. Healthy people were defined as disease-free checked by different imaging, blood tests and other pathological methods.

Exclusion criteria

i) Insufficient data; ii) TK1 immunohistochemistry and TK1 activity; iii) Invalid research data, which included physiological stress responses such as immunological reaction, inflammation and activation of metabolic adenosine mediators. Oxidative stress was considered a surgical stress response, together with myocardial injury, sepsis, pulmonary edema, and kidney and liver failure, which could increase mortality; iv) Healthy people were excluded when containing diseases associated with tumors proliferation, such as precancerous (moderate/severe types of hyperplasia of breast, prostate, gastrointestinal, cervix, liver cirrhosis, refractory anemia). Also excluded were people with risk-diseases associated with tumors progression such as liver disease, moderate/severe fatty liver, high risk for hepatitis B, abnormal liver function, obesity and benign tumors (such as renal, thyroid); and any of the following conditions: severe cardiac disease; using any medication that could affect the STK1 levels such as exogenous hormone therapy; pregnancy; or acute illness such as inflammation/virus infection within 4 weeks.

Literature screening and data extraction Primary screening

The title and abstract of literatures were carefully reviewed, and 10% of the excluded papers were randomly selected to check the concordance rate.

Secondary screening

After checking the abstracts, the full text of the papers was re-evaluated, and it was decided whether these papers should be included to the study or not, according to the criteria. Authors 1, 2 and 3 screened papers independently and discussed to reach an agreement; when met with a disagreement, the papers were rechecked by authors 5 and 6.

The following data were extracted from each study: First author's name, publication year, title of publication, published journal, study population, number of samples, design type and results.

Statistical analysis

RevMan 5.1 statistical software provided by Networks of Cochrane Review Groups and Stata 12.0 data analysis and statistical software were used (29). A heterogeneity test was performed at the beginning, and depending on the results, a fixed or random effects model was used. A fixed effects model with an I2 of <50% or random effects model with an I2 of >50% was used to calculate the weighted mean difference and 95% confidence interval. In addition, Funnel plot and Egger's linear regression test was used to assess literature bias. For the comparison of STK1p concentration among the different groups of controls and patients, one-way analysis of variance followed by a post hoc least significant difference test was performed. SPSS version 19 was utilized for statistical analysis (IBM Corp.). P<0.05 was considered to indicate a statistically significant difference.

Results

Literature search and study characteristics

The healthy control group included individuals with no evidence of tumors. Data from patients with colorectal neoplastic (adenomatous) polyps were used in the meta-analysis. Adenomatous polyps are benign tumors that originate from the mucus-secreting colonic epithelial cells (9). Tumors from CRC patients pathologically identified as clinical I-III degree and grade G1-G3 were defined as malignant. We had no information on whether other types of tumors besides CRC were identified in the benign or malignant tumor groups.

As shown in Fig. 1, a total of 314 publications were initially identified through a search of the Pubmed, Embase, CENTRAL, CNKI, Wanfang, VIP and SinoMed databases. A total 176 publications were removed due to duplications and 138 were kept. Next, 89 publications were excluded from the remaining articles following a screening of the titles and abstracts, due to being conference abstracts or focusing on unrelated topics. Therefore, 49 full-text articles were assessed for eligibility. Among them, 13 were excluded, since another STK1 method was used instead of the SSTK dot blot ECL assay, 7 because they used different endpoints, and 9 due to incomplete data. Finally, 20 studies were included in this meta-analysis (30-49).

Figure 1.

Figure 1

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Flow diagram of the literature search and study selection process.

The number of manuscripts, patients involved and the STK1p mean values in the control, benign and malignant tumor groups are shown in Table I. Detailed information on the number of cases, age distribution, type of CRC, clinical stages grades and just before start of the surgery and one month after surgery reported in the individual publications are presented in Table II.

Table I.

No of publications in the group of controls, benign and malignant persons, no of samples and STK1p mean values in the various groups included in the present study.

Variables Control Benign Malignant
Publications (n) 19 10 20
Samples (n) 1,701 774 1,836
STK1p (mean ± SD) 0.88±0.50 1.30±0.84 3.14±2.55
P-value 0.00078a <0.0001b <0.0001c
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P-values corresponding to the comparison of STK1p values between groups.

aControl vs. benigh group,

bbenigh vs. malignant group and

cmalignant vs. control group. SD, standard deviation; STK1p serum thymidine kinase 1.

Table II.

Summary of the clinical data included in each selected publication.

                Clinical stage (n) Pathological grading (n) CRC type Surgery
Author/(Ref), year Location Control (n) Benign (n) CRC (n) M (n) F (n) Age I II III Low diff. Medium/high diff. Colon Rectum Before After
An et al (36), 2016 Southwest 33   45 45   31-76     45     24 21 13 13
Huo et al (41), 2015 East China 32 35 76 51 25 36-83     76     76      
Li (46), 2012 Southwest 120 100 120 78 42 31-80     120     60 60 120 120
Li and Wang (49), 2009 East China 48 45 108 79 29 31-78     108       108    
Liu et al (40), 2015 South China 600 137 65 65   22-67     65     65      
Lu et al (44), 2014 South China 40 61 77 43 34 38-88     77     38 39    
Shen et al (47), 2011 East China 60 50 43 28 15 30-79     43     21 22 43 43
Tian et al (48), 2010 East China 33   66 45 21 25-72     66     66   66 66
Xia et al (39), 2015 East China 41   61 33 28 23-85     61 43 18 61   16 16
Qi et al (45), 2013 East China 45   104 104   32-81     104     52 52    
Zeng and Zhang (38), 2015 East China   103 133 77 56 32-84     133     133      
Zhang et al (42), 2015 Huazhong 40 36 150 88 62 30-78     150     150   150 150
Zhang et al (43), 2014 East China 161   64 64   35-84     64     35 29    
Zhu et al (35), 2017 Huazhong 52 162 82 49 33 36-68 17   65 34 48   82    
Zhu et al (37), 2015 East China 67   33 33   16-85 7 8 18       33 33 33
Fan et al (30), 2019 Northwest 60 45 50 23 27 60-70     50 31 19 50      
Jiang et al (32), 2018 East China 70   71 50 21 32-82 9 26 36 18 53 22 49    
Weng (31), 2018 South China 64   64 36 28 42-73 15 29 20       64    
Sun et al (33), 2018 Northeast 60   80 50 30 24-80     80 54 26 80      
Ning et al (34), 2018 South China 75   344 344     132   212     177 167    
Total number   1,701 774 1,836 1,385 451   180 63 1,593 180 164 1,110 726 441 441
Age distribution   16-85 35-84       23-85               30-85 30-85
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CRC, colorectal cancer; M, male; F, female; diff., differentiation.

A total of 1,836 CRC patients were included in the 20 publications, including 774 benign tumor patients and 1,701 healthy individuals. The majority of CRC patients were male with an age-distribution of 16-85 years and colon cancer clinical stage of III and grade low/medium/high. The expression of STK1p increased significantly in the following manner: Controls < benign < malign (P<0.001). The quality of the meta-analysis as a study was checked by the NOS and was found to be high, with 19 publications meeting 8 of the requirements of NOS, and 1 publication meeting 6. The results are presented in Table III.

Table III.

Literature quality evaluation by Newcastle-Ottawa Scale Document Quality Assessment Scale (NOS).

Author/(Ref), year Is the definition adequate? Representativeness of cases Section selection of controls Definition of controls Comparability of cases and controls on the basis of design and analysis Ascertainment of exposure Exposure same method of ascertainment for cases and controls Non-response rate
An et al (36), 2016 * * * * ** * * *
Huo et al (41), 2015 * * * * ** * * *
Li (46), 2012 * * * * ** * * *
Li and Wang (49), 2009 * * * * ** * * *
Liu et al (40), 2015 * * * * ** * * *
Lu et al (44), 2014 * * * * ** * * *
Shen et al (47), 2011 * * * * ** * * *
Tian et al (48), 2010 * * * * ** * * *
Xia et al (39), 2015 * * * * ** * * *
Zeng and Zhang (38), 2015 * *     ** * * *
Zhang et al (42), 2015 * * * * ** * * *
Zhang et al (43), 2014 * * * * * * * *
Zhu et al (35), 2017 * * * * ** * * *
Zhu et al (37), 2015 * * * * ** * * *
Qi et al (45), 2013 * * * * ** * * *
Fan et al (30), 2019 * * * * ** * * *
Jiang et al (32), 2018 * * * * ** * * *
Weng (31), 2018 * * * * ** * * *
Sun et al (33), 2018 * * * * ** * * *
Ning et al (34), 2018 * * * * ** * * *
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* and ** indicates that the eight quality test options were fullfiled in the studies. See more explanations at http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

STK1p values in different populations

The STK1p values were significantly different between healthy individuals and benign tumor patients, healthy individuals and CRC patients, and benign tumor and CRC patients (Table I, Fig. 2A). The number of publications involved among the healthy controls were 19, the benign 10 and the malignant 20, corresponding to 1,701, 774 and 1,836 persons, respectively. The STK1p values decreased significantly (40%) 1 month after surgery (Fig. 2B).

Figure 2.

Figure 2

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STK1p levels. (A) STK1p levels in healthy controls, benign patients and patients with malignant colorectal cancer patients. (B) STK1p levels in patients with malignant colorectal cancer before and after treatment. Data are presented as the mean ± standard deviation and significant values were determined using a t-test. STK1p, serum thymidine kinase 1.

Meta-analysis statistical calculation

Significant values were calculated using statistical programs for meta-analysis (see Material and methods sections). The results for the different test groups are shown in Figs. 3 and 4. The statistical values were calculated between healthy individuals and benign tumor patients (Fig. 3B), healthy individuals and CRC malignant tumor patients (Fig. 3A), benign and malignant tumor patients (Fig. 3C), and before and after surgery (Fig. 3D).

Figure 3.

Figure 3

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Forest plots for correlation analysis. Forest plots were assessed between (A) healthy controls vs. malignant patients, (B) healthy controls vs. CRC benign patients, (C) benign patients vs. CRC malignant patients and (D) before vs. after surgery. Black diamonds indicate the mean value. CRC, colorectal cancer; SD, standard deviation; CI, confidence interval; IV, inverse variation.

STK1p of healthy individuals compared to benign tumor patients

In this statistical calculation 1,052 healthy individuals and 671 benign tumor patients from 9 studies were used. Based on a random effects model, the heterogeneity test showed that the STK1p value in healthy individuals was significantly lower than that in benign tumor patients (Fig. 3B).

STK1p of healthy individuals compared to CRC patients

Of the 20 publications received, 19 were used in this comparison, including 1,701 healthy individuals and 1,703 patients with CRC (Fig. 3A). A heterogeneity test based on the random effects model showed that the STK1p value in CRC patients was statistically higher than that in healthy individuals.

STK1p in benign tumor patients compared to CRC patients

Out of the 20 publications, 10 included data regarding STK1p in benign tumors and CRC (Fig. 3C). There was a total of 774 cases in the benign tumor group and 904 in the CRC group. A heterogeneity test based on the random effects model showed that the STK1p values were significantly higher in CRC patients, as compared to benign tumor patients.

STK1p level before and after surgery

All 20 publications included data regarding the STK1p level before and 1 month after surgery. A heterogeneity test, based on the random effects model, showed a significant decrease by 40% 1 month after surgery (Fig. 3D).

Sensitivity analysis

Sensitivity analysis was conducted to evaluate the effect of excluding any individual study. By excluding 1 article at a time in turn, the summary results of the remaining literatures did not substantially change (Fig. 4A).

Figure 4.

Figure 4

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Study sensitivity analyses and the evaluation of mean differences. Evaluations were performed between (A) healthy control group and the colorectal malignancy group, (B) the benign disease and the colorectal malignancy group and (C) between the results obtained before and after surgery in the colorectal cancer group.

Publication bias

Begg's Funnel-plot (Fig. 4B) and Egger' test (Table IV) were used to examine the potential publication bias. There was no evidence of bias between the healthy individuals and the benign tumor group, healthy individuals and the malignant group, the benign and malignant tumor groups, or the before and after treatment groups. The Egger's test showed that the possibility of potential bias from each comparison analysis was very low (all P>0.05; Table IV). Based on these results, no significant publication bias was identified in this meta-analysis.

Table IV.

Egger's linear regression test for the assessment of publication bias.

Standard effect Coefficient Standard error T value p>|t| 95% CI
Control vs. benign          
     Slope -0.8601885 0.2631424 -3.27 0.014 -1.482421 to -0.2379556
     Bias 4.134483 2.616981 1.58 0.158 -2.053694 to 10.32266
Control vs. malignant          
     Slope -2.533914 0.249529 -10.15 0.000 -3.060375 to -2.007454
     Bias 1.303459 2.242794 0.58 0.569 -3.428422 to 6.03534
Benign vs. malignant          
     Slope -2.50849 0.6528756 -3.84 0.005 -4.014024 to -1.002956
     Bias 5.555459 4.287575 1.30 0.231 -4.331706 to 15.44262
Before vs. after treatment          
     Slope 1.414582 0.2186961 6.47 0.001 0.8524054 to 1.976758
     Bias -0.6030739 1.460007 -0.34 0.744 -4.256143 to 3.249995
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CI, confidence interval.

Discussion

Meta-analysis is a statistical analysis that combines the results of multiple studies (50-52). In the present study, a meta-analysis was performed according to the aforementioned inclusion and exclusion criteria. No bias was found. We also found that STK1p was able to distinguish between healthy individuals and benign tumor patients, as well as between healthy/benign tumor and malignant tumor patients. STK1p also monitored the results of the surgery. Thus, STK1p is a reliable biomarker for the prognosis of benign tumor and CRC patients, and a useful follow-up tool for surgery.

The STK1p was determined by an assay with a high sensitivity (0.80) and specificity (0.99), and an AUC value of 0.96. This assay is the most sensitive assay for TK1 in the serum on the market today (16). The mean value of STK1p in the benign tumor patients was 1.64-fold higher than that in healthy individuals, but significantly lower than that in CRC patients (1.60-fold). Although the mean STK1p value in benign tumor patients was higher than that in healthy individuals, there was a deviation, with both low and high individual STK1p values. The benign tumor patients with higher STK1p values (>2.0 pM) may be in a higher risk of developing malignancies than benign tumor patients with low STK1p values (<2.0 pM). Based on a health screening study (n=35,365) (18), where patients with a STK1p value of >2.0 pM were found to have a 3-5 times higher risk to develop a malignancy, we concluded that the risk for developing colorectal malignancies from a benign colorectal tumor should be higher in benign tumor patients with an STK1p value of >2.0 pM. On the other hand, benign tumor patients with STK1p values of <2.0 pM should have a low risk of developing CRC. STK1p was also found to have a prognostic potential in a randomised clinical trial that included patients with CRC (n=504) (28). Patients were followed up for 3-8 years. STK1p was compared with pathological stage and grade, lymph node metastasis, gender and age in relation to survival. A significantly worse survival was found among patients with high STK1p values (>0.9 pM), as compared to patients with low STK1p values (≤0.9 pM) (P<0.0001). Cox regression analysis demonstrated that STK1p, clinical stage and lymph node metastasis were independent prognostic factors, but Dukes' stage (P=0.633), sex (P=0.976) and age (P=0.520) were not.

In the present meta-analysis, the cut-off STK1p value was set to 0.9 pM, based on receiver operating characteristic statistical analysis. It is important to understand that the cut-off value of STK1p may differ depending on the type of tumor and how the measurement of STK1p was performed (healthy screening, clinical trials, etc.).

CRC is a heterogeneous disease, with most cases originating from polyp precursors. Different clinical stages and pathological grades of CRC can lead to heterogeneity.

CRC, a complex disease, is caused by both genetic and environmental factors. Certain studies have shown that inherited genetic factors account for ~35% of the disease etiology (53,54). It has been suggested that there may be two distinct categories of cancer: Right- and left-sided colon cancers that arise proximally or distally to the splenic flexure, respectively (55). A meta-analysis on vitamin E concentration in the serum suggested that serum vitamin E concentration was lower in patients with CRC than in healthy controls. Reduced serum vitamin E levels may therefore be a risk factor for CRC. However, prospective cohort studies are still required to assess the risk of serum vitamin E on CRC in the future (56). Although the original Dukes staging system has been modified several times, the extent of cancer invasion through the bowel wall and that of regional lymph node invasion is still the mainstay of TNM staging for CRC. A 17,641 patient-cohort study demonstrated that right- and left-sided colon carcinoma (CC) are significantly different in terms of epidemiological, clinical and histological parameters. Right-sided CC has been found to have a worse prognosis. These discrepancies may be due to genetic differences that determine distinct carcinogenesis and biological behaviour (57). There was no significant difference in recurrence rates between right- and left-sided CC and rectum carcinoma (RC), but the right-sided CC had a worse prognosis than left-sided CC and RC, possibly due to more advanced staging and fewer curative resections (58). Another study demonstrated that the patients with stage I right-sided CC had a significantly better 5 year disease free survival rate than those with left-sided CC; however, no significant difference was observed in the distribution of the first patients with recurrence (59). A retrospective design and single-institution study showed that patients with right-sided colon cancers presented with a significantly increased risk of locoregional recurrence. Right-sided location, female sex, T4 disease, lymph node metastasis, and perineural invasion are independent risk factors for the locoregional recurrence of colon cancer (60). Qin et al (61) found that right- and left-sided colon cancer had significantly different clinicopathological characteristics. Right-sided colon cancer had a higher incidence of recurrence than left-sided colon cancer. Patients with stage III right-sided colon cancer had a worse prognosis than those with stage III left-sided colon cancer. In addition, CRC results may vary from region to region, resulting in heterogeneity, depending on patients' genetic characteristics and living conditions.

With regard to the heterogeneity in the STK1 results, in a preliminary CRC study on 492 patients (Prof. Desong Wan, Sun Yet-Sen University Cancer Centre, China) no significant difference (P≈0.628-0.645) was found in the STK1 values between right-(n=91) and left-(n=124) side colon cancer, and rectum (n=277). The STK1p value of right colon, left colon and rectum was 1.8±1.8, 1.9±1.8 and 1.9±1.8 pM, respectively. STK1p is therefore useful for assessing the proliferation rate in CRC serum samples.

Monitoring the response to treatment is important. Previous studies have shown that STK1p can be used not only to predict prognosis, relapse and survival, but also to monitor tumor treatment (28). In this meta-analysis, the half-life time of STK1p following surgery was found to be ~1 month, which is the half-life time identified following surgery in patients with lung cancer (26) and gastric carcinoma (62). In the case of gastric carcinoma, the STK1p values were significantly reduced to 52.7% 35 days after open surgery (P=0.0106). On the contrary, in the patients with distant metastases, the STK1p value increased to 173% at 35 days post-operatively. There was no significantly difference in TK activity. Similar results were also found in breast cancer (20). However, in the case of minimally invasive surgery, the half-life time of STK1p in patients with bladder carcinoma was only 1 week (63).

It is recommend that STK1p is combined with other tools to evaluate the treatment effect on patients with CRC. This will help individual treatment planning. The following parameters in combination with STK1p should be considered when designing a CRC study: i) CRC is a heterogeneous disease (63), the majority of which is developed from polyp precursors. Therefore, a complete study should use tools useful for the early detection, diagnosis, prognosis and management of CRC development from benign tumors; ii) Since CC and RC are two different types of malignancy (64), they should be evaluated separately; the same goes for right- and left-sided CC and RC; iii) While monitoring the effect of the treatment, the STK1p levels may change depending on clinical stage/grade and tumor type on an individual bases; iv) Since CRC results may differ between living area, depending on the genetic properties and living conditions of the patients, studies should include data from different health centres and oncology hospitals.

In summary, STK1p could potentially be used for the early detection of benign lesions to prevent their future development into colorectal malignancies, as well as for individual clinical dynamic monitoring of the results of surgery in patients with CRC. The combination of STK1p with colorectal imaging tools after treatment can provide a precise evaluation of the results of the therapy. Together with the use of colorectal-related biomarkers, tumor stage and grade for predicting the risk of relapse, STK1p can help doctors develope more accurate, individualized and rational treatment plans for patients.

Acknowledgements

The authors would like to thank Professor Desong Wan from the Cancer Centre of Sun Yet-Sen University (Guangdong, China) for providing STK1p serum samples of CRC.

Funding

No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Authors' contributions

LD, HM, AH and SX searched the literature, independently extracted the data, produced the figures and tables, and discussed the articles until an agreement was reached. JZ, EH and SS carefully re-analyzed all results. LD, HM and AH wrote the first version of the manuscript. EH and SS revised the introduction and discussion sections of the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

JZ is the owner of SSTK Ltd., which produces the STK1p kit. Authors declare they have no competing interests.

References

  • 1.Boyle P, Levin B. World Cancer Report 2008. International Agency for Research on Cancer; Distributed by WHO Press, c2008, International Agency for Research on Cancer. France, Publisher: Lyon: Geneva, 2008. [Google Scholar]
  • 2.Stewart BW, Wild CP. World Cancer Report 2014. International Agency for Research on Cancer; World Health Organization. France, Publisher Lyon, 2014. [Google Scholar]
  • 3.Stewart BW, Bray F, Forman D, Ohgaki H, Straif K, Ullrich A, Wild CP. Cancer prevention as part of precision medicine: ‘Plenty to be done’. Carcinogenesis. 2016;37:2–9. doi: 10.1093/carcin/bgv166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Huxley RR, Ansary-Moghaddam A, Clifton P, Czernichow S, Parr CL, Woodward M. The impact of dietary and lifestyle risk factors on risk of colorectal cancer: A quantitative overview of the epidemiological evidence. Int J Cancer. 2009;125:171–180. doi: 10.1002/ijc.24343. [DOI] [PubMed] [Google Scholar]
  • 5.Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132. doi: 10.3322/caac.21338. [DOI] [PubMed] [Google Scholar]
  • 6.Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010;138:2044–2058. doi: 10.1053/j.gastro.2010.01.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Cappellani A, Zanghì A, D Vita M, Cavallaro A, Piccolo G, Veroux P, Lo Menzo E, Cavallaro V, de Paoli P, Veroux M, Berretta M. Strong correlation between diet and development of colorectal cancer. Front Biosci. 2013;18:190–198. doi: 10.2741/4095. [DOI] [PubMed] [Google Scholar]
  • 8.Abu-Remaileh M, Bender S, Raddatz G, Ansari I, Cohen D, Gutekunst J, Musch T, Linhart H, Breiling A, Pikarsky E, et al. Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer. Cancer Res. 2015;75:2120–2130. doi: 10.1158/0008-5472.CAN-14-3295. [DOI] [PubMed] [Google Scholar]
  • 9.Shussman N, Wexner SD. Colorectal polyps and polyposis syndromes. Gastroenterol Rep. 2014;2:1–15. doi: 10.1093/gastro/got041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L, Kunkler I. Recent cancer survival in Europe: A 2000-02 period analysis of EUROCARE-4 data. Lancet Oncol. 2007;8:784–796. doi: 10.1016/S1470-2045(07)70246-2. EUROCARE-4 Working Group. [DOI] [PubMed] [Google Scholar]
  • 11.Ciccolallo L, Capocaccia R, Coleman MP, Berrino F, Coebergh JW, Damhuis RA, Faivre J, Martinez-Garcia C, Møller H, Ponz de Leon M, et al. Survival differences between European and US patients with colorectal cancer: Role of stage at diagnosis and surgery. Gut. 2005;54:268–273. doi: 10.1136/gut.2004.044214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  • 13.Binefa G, Rodríguez-Moranta F, Teule A, Medina-Hayas M. Colorectal cancer: From prevention to personalized medicine. World J Gastroenterol. 2014;20:6786–6808. doi: 10.3748/wjg.v20.i22.6786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Ribero D, Viganò L, Amisano M, Capussotti L. Prognostic factors after resection of colorectal liver metastases: From morphology to biology. Future Oncol. 2013;9:45–57. doi: 10.2217/fon.12.159. [DOI] [PubMed] [Google Scholar]
  • 15.Gasparri F, Wang N, Skog S, Galvani A, Eriksson S. Thymidine kinase 1 expression defines an activated G1 state of the cell cycle as revealed with site-specific antibodies and arrayscan assays. Eur J Cell Biol. 2009;88:779–785. doi: 10.1016/j.ejcb.2009.06.005. [DOI] [PubMed] [Google Scholar]
  • 16.Zhou J, He E, Skog S. The proliferation marker thymidine kinase 1 in clinical use. Mol Clin Oncol. 2013;1:18–28. doi: 10.3892/mco.2012.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Cao X, Zhou J, Chen Z. Standardized centile curves and reference intervals of serum thymidine kinase 1 levels in a normal Chinese population using the LMS method. Genet Test Mol Biomarkers. 2016;20:445–450. doi: 10.1089/gtmb.2015.0288. [DOI] [PubMed] [Google Scholar]
  • 18.Chen ZH, Huang SQ, Wang Y, Yang AZ, Wen J, Xu XH, Chen Y, Chen QB, Wang YH, He E, et al. Serological thymidine kinase 1 is a biomarker for early detection of tumours-a health screening study on 35,365 people, using a sensitive chemiluminescent dot blot assay. Sensors (Basel) 2011;11:11064–11080. doi: 10.3390/s111211064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.He Q, Zhang P, Zou L, Li H, Wang X, Zhou S, Fornander T, Skog S. Concentration of thymidine kinase 1 in serum (S-TK1) is a more sensitive proliferation marker in human solid tumors than its activity. Oncol Rep. 2005;14:1013–1019. [PubMed] [Google Scholar]
  • 20.He Q, Fornander T, Johansson H, Johansson U, Hu GZ, Rutqvist LE, Skog S. Thymidine kinase 1 in serum predicts increased risk of distant or loco-regional recurrence following surgery in patients with early breast cancer. Anticancer Res. 2006;26:4753–4759. [PubMed] [Google Scholar]
  • 21.Kumar JK, Aronsson AC, Pilko G, Zupan M, Kumer K, Fabjan T, Osredkar J, Eriksson S. A clinical evaluation of the TK 210 ELISA in sera from breast cancer patients demonstrates high sensitivity and specificity in all stages of disease. Tumour Biol. 2016;37:11937–11945. doi: 10.1007/s13277-016-5024-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Liu Y, Ling Y, Qi Q, Tang Y, Xu J, Tong Z, Sheng G, Yang Q, Pan Y. Changes in serum thymidine kinase 1 levels during chemotherapy correlate with objective response in patients with advanced gastric cancer. Exp Ther Med. 2011;2:1177–1181. doi: 10.3892/etm.2011.338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Chen F, Tang L, Xia T, He E, Hu G, Zhang M, Li Y, Zhou J, Eriksson S, Skog S. Serum thymidine kinase 1 levels predictcancer-free survival following neoadjuvant, surgical and adjuvant treatment of patients with locally advanced breast cancer. Mol Clin Oncol. 2013;1:894–902. doi: 10.3892/mco.2013.149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Aufderklamm S, Hennenlotter J, Todenhoefer T, Gakis G, Schilling D, Vogel U, Kuehs U, Dlugosch J, Knapp J, Merseburger A, et al. XPA-210: A new proliferation marker determines locally advanced prostate cancer and is a predictor of biochemical recurrence. World J Urol. 2012;30:547–552. doi: 10.1007/s00345-011-0768-y. [DOI] [PubMed] [Google Scholar]
  • 25.Wang Y, Jiang X, Dong S, Shen J, Yu H, Zhou J, Li J, Ma H, He E, Skog S. Serum TK1 is a more reliable marker than CEA and AFP for cancer screening survey in a study of 56,286 people. Cancer Biomark. 2016;16:529–536. doi: 10.3233/CBM-160594. [DOI] [PubMed] [Google Scholar]
  • 26.Lou X, Zhou J, Ma H, Xu S, He E, Skog S, Wang H. The half-life of serum thymidine kinase 1 concentration is an important tool for monitoring surgical response in patients with lung cancer: A meta-analysis. Genet Test Mol Biomarkers. 2017;21:471–478. doi: 10.1089/gtmb.2017.0003. [DOI] [PubMed] [Google Scholar]
  • 27.Yurish SY. Serum-biomarker thymidine kinase 1 for early discovery of tumour process -160,086 participants using a sensitive immune-ECL-dot-blot detection system. Advances in Sensors: Reviews. 2018;6:529–540. http://www.sensorsportal.com. [Google Scholar]
  • 28.Skog S, He E, Haghdoost S. Prevention and early detection of human tumour. LAP lambert academic publishing, Schaltungsdienst Lange O.H.G., Berlin. p74, p183-257. www.get-morebook.com. [Google Scholar]
  • 29.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Fan XJ, Shi ZT, Sun W. Significance of TuM2-PK, TK1, CEA, CA19-9 and CA72-4 in the diagnosis of colon cancer patients. Chin J Gerontol. 2019;39:51–53. [Google Scholar]
  • 31.Weng YL. Diagnostic value of serum TuM2-PK, TK1 and HER-2 expression levels in rectal cancer. Henan Med Res. 2018;1:1795–1797. [Google Scholar]
  • 32.Jiang XL, Bo YX, Ye Y. Correlation between TK1 and tumor markers in diagnosis and pathological features of digestive tract tumors. J Anhui Med Univ. 2018;53:110–114. [Google Scholar]
  • 33.Sun HW, Mei M, Liu YY, Liu XZ. Clinical value of serum thymidine kinase 1 in the evaluation of chemotherapy for stage IV colon cancer. Continuing Medical Education. 2018;8:81–83. [Google Scholar]
  • 34.Ning S, Wei W, Li J, Hou B, Zhong J, Xie Y, Liu H, Mo X, Chen J, Zhang L. Clinical significance and diagnostic capacity of serum TK1, CEA, CA 19-9 and CA 72-4 levels in gastric and colorectal cancer patients. J Cancer. 2018;3:494–501. doi: 10.7150/jca.21562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Zhu LP, Li XL, Liu H, Ping YF, Zhang YN. Expression and clinical significance of thymidine kinase 1 in rectal cancer. J Xiangnan Univ (Medical Sciences) 2017;19:9–12. [Google Scholar]
  • 36.An N, Zhang M, Lan HT, Li HM. Significance of detecting serum thymidine kinase 1 in metastatic large intestine carcinoma before and after chemotherapy. Med J West China. 2016;28:1257–1260. [Google Scholar]
  • 37.Zhu YZ, Ma T, Zhang CJ, Sun GP. The expression and clinical significance of serum thymidine kinase 1 in cancer patients. Acta Univ Med Anhui. 2015;7:1012–1015. [Google Scholar]
  • 38.Zeng QH, Zhang SY. Diagnostic value of combined detection of CEA, CA199 and TK1 for colorectal cancer. Med Equipment. 2015;10:2–4. [Google Scholar]
  • 39.Xia Y, Liu Y, Qi Q, Zhu M, Zhang Y, Ling Y. Value of serum thymidine kinase 1 in the chemotherapy efficacy evaluation for patients with stage IV colon cancer. J Basic Clin Oncol. 2015;28:6–8. [Google Scholar]
  • 40.Liu X, Feng Z, Lai Z, Jiang Y, Xu M, Zhou X. An analysis on expression difference of serum TK1 between patients with gastric carcinoma, lung cancer, colon cancer and healthy person and its clinical significance. J Mathematical Med. 2015;58:913–915. [Google Scholar]
  • 41.Huo Y, Yu X, Kong AP. The application value of TK1 in colon cancer patients. Int J Lab Med. 2015;36:3151–3152. [Google Scholar]
  • 42.Zhang Y, Wang J, Xie J, Yang D, Han G, Zhang Y. The assay and clinical significance of serum thymidine kinase 1 in patients with colorectal carcinoma. Eur Surg. 2015;47:248–253. [Google Scholar]
  • 43.Zhang ZJ, Zheng YP, Lin YH, Mei XQ. Clinical detecting application of TK1 in the diagnosis of common malignant tumors. Int J Lab Med. 2014;35:2636–2637. [Google Scholar]
  • 44.Lu ZQ, Xie YM, Cheng GH, Li JH. Clinical diagnostic value of combined detection of serum TK1, CAl99 and CA724 in colorectal cancer. China Practical Medicine. 2014;9:5–7. [Google Scholar]
  • 45.Qi QF, Zhu M, Bao YQ, Liu YP. Detection of serum TK1 in patients with colorectal cancer after operation to evaluate the effect of value. World Latest Med Information. 2013;13:60–61. [Google Scholar]
  • 46.Li QF. Clinical application of serum thymidine kinase 1 used in colorectal carcinoma patients. Laboratory Med. 2012;27:1080–1081. [Google Scholar]
  • 47.Shen J, Chen W, Xu RH, Zhang JF, Jiang H. Evaluation of the significance of serum thymidine kinase 1 detection in the diagnosis and curative effect of gastrointestinal malignant tumors. Exp Lab Med. 2011;29:531–533. [Google Scholar]
  • 48.Tian J, Jia Y, Liu H. Serum TK1, EGF, HGF and CRP and IL-6 levels in patiens with colon cancer using laparoscopic and open surgery. Shangdong Med. 2010;50:42–43. [Google Scholar]
  • 49.Li X, Wang F. Significance of serum thymidine kinase determination in patients with carcinoma of rectum. Jiangsu Medical J. 2009;35:1436–1437. [Google Scholar]
  • 50.Streiner DL. I have the answer, now what's the question?: Why meta-analyses do not provide definitive solutions. Can J Psychiat. 2005;50:829–831. doi: 10.1177/070674370505001304. [DOI] [PubMed] [Google Scholar]
  • 51.Chatterji M. Grades of evidence: Variability in quality of findings in effectiveness studies of complex field interventions. Am J Eval. 2007;28:239–255. [Google Scholar]
  • 52.Baas M, De Dreu CK, Nijstad BA. A meta-analysis of 25 years of mood-creativity research: Hedonic tone, activation, or regulatory focus? Psychol Bull. 2008;134:779–806. doi: 10.1037/a0012815. [DOI] [PubMed] [Google Scholar]
  • 53.Zou L, Zhang PG, Zou S, Li Y, He Q. The half-life of cytosolic thymidine kinase in serum by ECL dot bolt potential marker for monitoring the response to surgery of patients with gastric cancer. Int J Biol Markers. 2002;17:135–140. doi: 10.5301/jbm.2008.1382. [DOI] [PubMed] [Google Scholar]
  • 54.Zhang J, Jia Q, Zou S, Zhang P, Zhang X, Skog S, Luo P, Zhang W, He Q. Thymidine kinase 1: A proliferation marker for determining prognosis and monitoring the surgical outcome of primary bladder carcinoma patients. Oncol Rep. 2006;15:455–461. [PubMed] [Google Scholar]
  • 55.Ogino S, Chan AT, Fuchs CS, Giovannucci E. Molecular pathological epidemiology of colorectal neoplasia: An emerging transdisciplinary and interdisciplinary field. Gut. 2011;60:397–411. doi: 10.1136/gut.2010.217182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Dong Y, Liu Y, Shu Y, Chen X, Hu J, Zheng R, Ma D, Yang C, Guan X. Link between risk of colorectal cancer and serum vitamin E levels: A meta-analysis of case-control studies. Medicine (Baltimore) 2017;96(e7470) doi: 10.1097/MD.0000000000007470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Benedix F, Kube R, Meyer F, Schmidt U, Gastinger I, Lippert H. Comparison of 17,641 patients with right- and left-sided colon cancer: Differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53:57–64. doi: 10.1007/DCR.0b013e3181c703a4. Colon/Rectum Carcinomas (Primary Tumor) Study Group. [DOI] [PubMed] [Google Scholar]
  • 58.Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K. Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2019;343:78–85. doi: 10.1056/NEJM200007133430201. [DOI] [PubMed] [Google Scholar]
  • 59.Hemminki K, Chen B. Familial risk for colorectal cancers are mainly due to heritable causes. Cancer Epidemiol Biomarkers Prev. 2004;13:1253–1256. [PubMed] [Google Scholar]
  • 60.Moritani K, Hasegawa H, Okabayashi K, Ishii Y, Endo T, Kitagawa Y. Difference in the recurrence rate between right- and left-sided colon cancer: A 17 year experience at a single institution. Surg Today. 2014;44:1685–1691. doi: 10.1007/s00595-013-0748-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Qin Q, Yang L, Sun YK, Ying JM, Song Y, Zhang W, Wang JW, Zhou AP. Comparison of 627 patients with right- and left-sided colon cancer in China: Differences in clinicopathology, recurrence, and survival. Chronic Dis Transl Med. 2017;13:51–59. doi: 10.1016/j.cdtm.2017.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Zou L, Zhang PG, Zou S, Li Y., He Q. The half-life of cytosolic thymidine kinase in serum by ECL dot blot potential marker for monitoring the response to surgery of patients with gastric cancer. International Journal of Biological Markers. 2002;17:135–140. doi: 10.5301/jbm.2008.1382. [DOI] [PubMed] [Google Scholar]
  • 63.Zhang J, Jia Q, Zou S, Zhang P, Zhang X, Skog S, Luo P, Zhang W, He Q. Thymidine kinase 1: a proliferation marker for determining prognosis and monitoring the surgical outcome of primary bladder carcinoma patients. Oncology Reports. 2006;15:455–461. [PubMed] [Google Scholar]
  • 64.Paschke S, Jafarov S, Staib L, Kreuser ED, Maulbecker-Armstrong C, Roitman M, Holm T, Harris CC, Link KH, Kornmann M. Are colon and rectal cancer two different tumor entities? A proposal to abandon the term colorectal cancer. Int J Mol Sci. 2018;19(E2577) doi: 10.3390/ijms19092577. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

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