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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 3  |  Page : 104-110

YKL-40 in high-grade glioma: Prognostic value of protein versus mRNA expression


1 Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
2 Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
3 Center for Evidence-based and Translational Medicine, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
4 Department of Neurosurgery, Laboratory of Neuro-Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. Zhi-Qiang Li
Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan 430072, Hubei
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_16_18

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  Abstract 

Background: YKL-40 has been reported to be associated with the prognosis of glioma patients. However, expression of YKL-40 was detected at protein or mRNA level in different studies. This may result in conclusion bias. This study is to investigate the prognostic value of increased YKL-40 protein versus mRNA expression in glioma patients. Methods: A comprehensive systematic search and review were performed using PubMed, EMBASE, and NKI databases to identify literature (published before May 1, 2018) that evaluated the association between YKL-40 and survival in glioma patients. Results: Thirteen relevant studies, involving 2139 patients, were included in this study. Elevated YKL-40 expression was associated with worse overall survival (OS) in glioma patients (hazard ratio [HR] = 1.44, 95% confidence interval [CI]: 1.27–1.63, P < 0.001), especially in high-grade glioma (anaplastic glioma: HR = 1.37, 95% CI: 1.09–1.74, P = 0.008; glioblastoma multiform: HR = 1.52, 95% CI: 1.33–1.73, P < 0.001). The increased YKL-40 protein level in serum (detected by ELISA) or in tumor tissues (detected by immunohistochemistry) was associated with worse OS (ELISA: HR = 1.43, 95% CI: 1.29–1.59, P < 0.001; immunohistochemistry: HR = 1.52, 95% CI: 1.20–1.93, P = 0.001). However, the association between elevated YKL-40 mRNA level (detected by real-time PCR) with worse OS was not significant (HR = 1.44, 95% CI: 0.73–2.83, P = 0.29, I2 = 68.3%). In addition when status of IDH1 mutation or/and O6-methylguanine-DNA methyltransferase promoter was incorporated as multivariate, increased expression level of YKL-40 was not associated with poorer survival (HR = 1.39, 95% CI: 0.99–1.93, P = 0.055). Conclusion: YKL-40 protein level, rather than mRNA level, may be a valuable biomarker to assess the prognosis in glioma patients.

Keywords: Glioma, prognosis, YKL-40


How to cite this article:
Zhao YH, Pan ZY, Wang ZF, Ma C, Weng H, Li ZQ. YKL-40 in high-grade glioma: Prognostic value of protein versus mRNA expression. Glioma 2018;1:104-10

How to cite this URL:
Zhao YH, Pan ZY, Wang ZF, Ma C, Weng H, Li ZQ. YKL-40 in high-grade glioma: Prognostic value of protein versus mRNA expression. Glioma [serial online] 2018 [cited 2022 Nov 30];1:104-10. Available from: http://www.jglioma.com/text.asp?2018/1/3/104/235649


  Introduction Top


Gliomas are the most common primary brain tumors in adults. Glioblastoma multiforme (GBM) is the most aggressive type of gliomas, and the median survival of GBM patients is only 14.6 months.[1] Low-grade gliomas are inevitably recurring and transform to a more malignant phenotype, and the prognosis of glioma patients may vary significantly despite being classified under the same tumor grade.[2] This indicates that the intrinsic genetic variations of GBM are complicated. Currently, genome-wide molecular profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of glioma. Many molecular biomarkers, such as O 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase 1 (IDH1) mutations, were recently verified as the valuable factors to assess the prognosis of GBM patients.[2],[3],[4]MGMT promoter methylation and IDH1 mutations in GBM patients conferred a favorable treatment response to temozolomide chemotherapy and longer survival.[5],[6]

Although MGMT promoter methylation and IDH1 mutations are widely accepted as the important molecular biomarkers, the challenge of testing techniques hampered their widespread application. Therefore, other potential biomarkers with less challenge of the testing technique are being explored in recent years. YKL-40, also known as human cartilage glycoprotein 39 or chitinase 3-like 1, is a chitinase homolog. It is secreted by numerous human cells such as endothelial cells, inflammatory cells,[7] and cancer cells.[8] Previous studies have associated high level of YKL-40 protein in serum, detected by ELISA, with poor overall survival (OS) in high-grade glioma patients.[9],[10],[11],[12] Some reports also showed that glioma patients with high mRNA level of YKL-40 had a bad survival rate.[13],[14],[15] Meanwhile, some studies also reported that GBM patients with positive YKL-40 expression in tumor, detected by immunohistochemistry (IHC), also had a short survival.[16],[17],[18] The previous meta-analysis revealed that YKL-40 is a good predictive biomarker of prognosis in glioblastoma patients.[19] However, different forms of YKL-40 expression (protein vs. mRNA) were measured by different testing techniques in different studies, which may result in the bias of research conclusion. Moreover, the impact of MGMT promoter methylation and IDH1 mutations on the prognostic value of YKL-40 is not well defined.

Thus, we conducted a comprehensive analysis to determine whether high-protein level or the mRNA level of YKL-40, detected by varied methods, were associated with the survival of glioma patients and whether the predictive value of YKL-40 was affected by other molecular biomarkers. This meta-analysis will provide an updated and precise review on the clinical value of YKL-40 on survival in glioma patients.


  Methods Top


This systematic review was conducted according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline [Supplementary Table 1] [Additional file 1].[20]

Eligibility criteria

We evaluated the eligible studies only if all the following conditions were met: (1) studies determining the association between the YKL-40 and prognosis of glioma patients; (2) HR and 95% confidence intervals (CIs) for OS were provided or could be computed from the data presented; and (3) different testing methods were included.

Search strategy

We performed a systematic review to identify articles from PubMed, EMBASE, and NKI database for all articles covering the association between YKL-40 and prognosis of glioma patients. The articles enrolled in analysis were published before May 1, 2018. Our search included the Mesh Term: “Glioma” and “CHI3 L1”, and the following non-Mesh terms were used: (1) “Gliomas”, “Glial Cell Tumors”, “Glial Cell tumor”, “Mixed Glioma”, “Glioma, Mixed”, “Gliomas, Mixed”, “Mixed Gliomas”, “Malignant Glioma”, “Glioma, Malignant”, “Gliomas, Malignant”, “Malignant Gliomas”; (2) “CHI3 L1 protein, human”, “human cartilage gp39”, “human cartilage glycoprotein-39”, “38 kDa heparin-binding glycoprotein, human”, “YKL-40 protein, human”, “chitinase3-like 1, human”, “HCGP39 protein, human”, “HC-gp39 protein, human”, “chitinase3-like 1 (cartilage glycoprotein-39) protein, human”, “GP39 protein, human”, and “cartilage gp-39, human”. Reviews and the references of included studies were also checked to avoid omission of relevant publication. Studies were restricted to human beings.

Study selection and data extraction

Studies were selected by two independent reviewers. Disagreements were resolved through discussion among the authors to achieve a consensus. Publications were read to check original data extraction. The following information was extracted: the author's name, county, publications year, number of patients, adjusted factors, study design feature, outcomes (including hazard ratios [HRs], 95% CI). If the eligible studies provided both univariate and multivariate analysis, HRs were preferred by multivariate analysis as the multivariate values had higher precision on interpreting confounding factors in the Cox regression model.

Quality assessment

Newcastle Ottawa Scale (NOS) was used to evaluate the quality and risk of bias of included studies. The assessment of included studies was independently conducted by two reviewers. There were three main aspects including study selection (0–4 points), comparability (0–2 points), and study outcomes (0–3 points). High scores indicate high quality and low risk of bias.

Statistical analysis

The statistical analysis was performed by STATA 12.0 software (StataCorp, College Station, TX, USA). Time-to-event data (e.g., OS) was analyzed using the HRs. The statistical heterogeneity among studies was assessed with Q- test and I2 statistics.[21] Subgroup analysis was performed to evaluate the possible source of heterogeneity and further analysis of preliminary result. If there was no obvious heterogeneity, the fixed model was used to estimate the pooled HR;[22] otherwise, the random-effects model was used.[23] Publication bias was assessed by visually examining the funnel plots and by Egger's test.[24] Sensitivity analysis was performed by considering the risk of bias of studies. A trim and fill method was applied to estimate asymmetry in the funnel plot.[25]


  Results Top


Characteristics of included studies

With the aforementioned eligibility criteria, 265 articles were screened. The flowchart of literature selection is presented in [Figure 1]. Thirteen articles were initially included and were further assessed by reading full text.[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[26],[27],[28] One article was excluded for its uncertain data.[28] After quality assessment by NOS [Table 1], another two articles were excluded from meta-analysis in which multivariate analysis was not used to control important prognosis factors.[13],[26] Three articles comprising two individual trials were extracted as six individual studies.[11],[12],[17] Finally, 13 studies comprising 2139 patients in 10 articles were included into the meta-analysis.[9],[10],[11],[12],[14],[15],[16],[17],[18],[28] The characteristics of the studies are summarized in [Table 2].
Figure 1: Flow diagram of study selection

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Table 1: Quality assessment of included articles using the Newcastle Ottawa Scale for cohort studies

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Table 2: Characteristics of included studies

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Association of YKL-40 with overall survival of glioma patients

Meta-analysis of the included 13 studies showed that glioma patients with higher expression level of YKL-40 had a worse OS [HR = 1.44, 95% CI: 1.27–1.63, P < 0.001, I2 = 57.4%, [Figure 2]. We further evaluate the impact of YKL-40 on OS in glioma patients with different pathological grades. Among the included studies, ten studies were conducted in GBM patients, two studies were conducted in anaplastic glioma [11],[12] and one study were conducted in patients with different grade glioma.[15] The association of higher YKL-40 expression with worse OS was observed both in anaplastic glioma and in GBM patients [anaplastic glioma: HR = 1.37, 95% CI: 1.09–1.74, P = 0.008, I2 = 0%; GBM: HR = 1.52, 95% CI: 1.33–1.73, P < 0.001, I2 = 33.7%, [Figure 3].
Figure 2: Calculated hazard ratios and 95% confidence intervals for the relationship between YKL-40 and overall survival of glioma patients

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Figure 3: Calculated hazard ratios and 95% confidence intervals for the relationship between YKL-40 and overall survival in glioma patients with different pathological grades

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Among included studies, expression of YKL-40 was defined as protein level or mRNA level. Different testing methods were used in these studies. ELISA was used to measure serum YKL-40 protein concentration in six studies,[9],[10],[11] IHC was used to evaluate YKL-40 protein level in tumor tissue in five studies,[12],[16],[17],[18],[28] and real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure YKL-40 mRNA level in tumor tissue in two studies.[14],[15] Subgroup analysis was conducted to investigate whether high expression level of YKL-40 detected by different testing methods has the same prognostic value for glioma patients. No significant correlation was seen between elevated YKL-40 mRNA level and OS in glioma patients [HR = 1.44, 95% CI: 0.73–2.83, P = 0.29, I2 = 68.3%, [Figure 4]. However, patients who had elevated YKL-40 protein levels in serum or in tumor tissues had a shorter OS [ELISA: HR = 1.43, 95% CI: 1.29–1.59, P < 0.001, I2 = 0%; IHC: HR = 1.52, 95% CI: 1.20–1.93, P = 0.001, I2 = 58.1%, [Figure 4]. We also noticed that studies measuring serum YKL-40 by ELISA had better heterogeneity (I2 = 0%) than those measuring YKL-40 expression in tumor tissue by IHC (I2= 58.1%). These results indicate that protein level of YKL-40 in serum or in tumor tissues rather than mRNA level in tumor tissue may function as a biomarker for the prognosis of glioma patients.
Figure 4: Calculated hazard ratios and 95% confidence intervals for the relationship between YKL-40 detected by different testing methods and overall survival for glioma patients

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Effect of O 6-methylguanine-DNA methyltransferasemethylation or isocitrate dehydrogenase 1 mutation status on the prognostic value of YKL-40 in glioma patients

It is well known that the prognosis of glioma patients is affected by many factors, including age, tumor grade, MGMT methylation status, IDH1 mutation status. Therefore, whether YKL-40 protein is an independent biomarker for the prognosis of glioma patients was investigated. Multivariate Cox analysis was adopted in all included studies. Three studies incorporated the status of MGMT promoter methylation or IDH1 mutation into multivariate Cox analysis to evaluate the impact of YKL-40 on OS in glioma patients.[10],[18],[28] Subgroup analysis showed that higher protein level of YKL-40 was associated with worse OS when MGMT methylation and IDH1 mutation status were not incorporated as confounding variables [HR = 1.46, 95% CI: 1.27–1.69, P < 0.001, I2 = 58.4%, [Figure 5]. However, the higher risk of death was not shown in glioma patients with elevated expression of YKL-40 when MGMT methylation or IDH1 mutation status was taken into account as confounding variables [HR = 1.39, 95% CI: 0.99–1.93, P = 0.055, I2 = 68.1%, [Figure 5].
Figure 5: Impact of O6-methylguanine-DNA methyltransferase methylation and isocitrate dehydrogenase 1 mutation status on survival benefit of YKL-40

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Publication bias

Publication bias was observed in high-quality studies on the association between high expression of YKL-40 and OS in glioma patients [Egger's test, P = 0.006, [Figure 6]. Therefore, we need to use a trim and fill method to estimate the asymmetry in the funnel plot. The results remain unchanged after introducing the trim and fill method to correct the publication bias.
Figure 6: Egger's test for publication bias

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Sensitivity analysis

Sensitivity analysis was conducted by sequentially omitting individual studies to assess whether a single study might significantly affect the overall results. Sensitivity analysis showed that no apparent variations in pooled HR [Figure 7], supporting the robustness of the primary findings.
Figure 7: The result of sensitivity analysis

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  Discussion Top


YKL-40 has been reported as a potential prognostic marker for GBM patients in many original studies [9],[10],[14],[15],[16],[18],[28] and previous meta-analysis.[19] However, the role of YKL-40 in WHO Grade II and Grade III gliomas remain undefined. Some researchers demonstrated that YKL-40 could not be detected in WHO Grade II and Grade III gliomas,[29] while others showed that serum YKL-40 could be detected by ELISA in Grade III glioma patients. Meanwhile, the expression of YKL-40 was measured by different testing methods in different studies. Some studies measured serum YKL-40 protein concentration by ELISA,[9],[10],[11] some studies detected YKL-40 expression in tumor tissue by IHC,[12],[16],[17],[18],[28] and others detected the mRNA level in tumor tissue by RT-qPCR.[14],[15] Whether, the different methods employed to detect YKL-40 could influence the effective prediction of the prognosis in glioma patients is not yet studied.

Although our primary analysis showed that glioma patients with elevated expression of YKL-40 had a bad OS, which are consistent with previous results, subgroup analysis revealed that the association of higher YKL-40 expression with worse OS was only observed in anaplastic glioma and GBM patients. However, it must be noted that only two studies on anaplastic glioma were enrolled for analysis. We suggest that more studies including anaplastic gliomas should be performed in future. Another interesting result of this meta-analysis is that only high serum protein level of YKL-40 was found to be associated with short OS in glioma patients. The relationship between increased YKL-40 mRNA level and OS was not observed in glioma patients. This is the first report to illustrate the impact of varied detection methods of YKL-40 on its prognostic value. It is well known that mRNA levels may not always be consistent with protein expression due to the complex modulation mechanism during mRNA to protein translation. Therefore, our current results suggest that YKL-40 protein level in serum or in tumor tissues can more effectively predict the prognosis of glioma patients. In addition, the results of I2 statistics showed a better heterogeneity of studies in which serum YKL-40 was assayed by ELISA, convincing the significance of serum YKL-40 as a predictor in glioma prognosis. In this analysis, we also found that both WHO Grade III gliomas and GBM patients with elevated protein level of YKL-40, detected by ELISA, had a worse survival. Thus, we suggest that the high level of serum YKL-40 in high-grade glioma patients might be a hint of increased risk of bad OS. However, the time point of YKL-40 detection should also be defined further. In the included studies, some studies assessed YKL-40 protein level in tissue at the time of glioma diagnosis,[14],[15],[16],[17],[18],[28] while in other studies, protein level in serum was detected at multiple preoperative and postoperative time points during treatment.[9],[10],[11],[12] Dynamic monitoring of serum YKL-40 can be a more efficient way to evaluate patients OS. In fact, more related studies also focus on the possibility of YKL-40 protein as a serum biomarker to evaluate the effect of the target therapy. YKL-40 is shown to promote glioma invasion, migration [30],[31] and angiogenesis.[32],[33] Because of the pro-angiogenic function of YKL-40, through upregulating vascular endothelial growth factor,[32],[33] the results of a Phase III randomized trial (AVAglio) encourages the use of plasma YKL-40 as a biomarker to evaluate the efficacy of bevacizumab in GBM.[10] Recent increasing evidence support that circulating proteins may act as biomarkers for differential diagnosis and monitoring of GBM course and therapeutic efficacy.[34]

Another interesting issue of this study is the interpretation of independent or dependent clinical value of YKL-40 in glioma patients. MGMT promoter methylation and IDH1 mutation have been established as clinically relevant prognosis factors. Therefore, to account for the value of YKL-40 as a new molecular biomarker, it is essential to analyze the influence of MGMT promoter methylation and IDH1 mutation. Our results showed that higher YKL-40 expression was not associated with worse OS in glioma patients when MGMT methylation and IDH1 mutation status were included into multivariate analysis as confounding variables. Gliomas with IDH1 mutation or MGMT promoter methylation show better outcome than those with IDH1-wildtype or MGMT promoter unmethylation, which may possibly explain why YKL-40 protein levels are not sensitive to predict patient survival under multivariate analysis. Our results indicate that MGMT promoter methylation and IDH1 mutation may have an effect on the actions of YKL-40. YKL-40 plays a role in cell proliferation by activation of PI3K/AKT pathway,[35] and its expression could be regulated by nuclear factor-κB (NF-κB) activation.[36] However, previous studies have shown that IDH1 mutation and MGMT promoter methylation may regulate PI3K/Akt and NF-κB signaling.[37],[38],[39] Therefore, the crosstalk between YKL-40 and IDH1 mutation or MGMT promoter methylation may be an important factor to explain the value of YKL-40 in GBM with IDH1 mutation or MGMT promoter methylation. Further studies are needed to unravel such association. It should be noted that only three studies were enrolled in this subgroup analysis. Therefore, further clinical trials should incorporate prognostic molecular biomarkers, such as MGMT, IDH1/ 2, TERT, into the analysis.

In addition, to ensure the quality of involved studies and the reliability of pooled results, we set exacting inclusion criteria and quality assessment, and three studies with low quality due to unadjusted confounding factors were excluded from the study. However, limitations in this study should be acknowledged. First, different cutoff values for YKL-40 positive expression detected by IHC and RT-qPCR might contribute to the heterogeneity. Second, though there was no obvious risk of publication bias in the meta-analysis and retrospective studies demonstrated a possible source, the publication bias can also be an inevitable issue where the studies with positive results are easier to be published. By trim and fill analysis, the reliability of our results was upheld. Third, studies on YKL-40 mRNA level and multivariate analysis involving YKL-40, MGMT or/and IDH1 are limited, which make the related results not strongly convincing.

In conclusion, this study suggests that YKL-40 protein level, rather than mRNA level, may be a valuable biomarker to assess the prognosis in glioma patients. To comprehensively evaluate whether YKL-40 is independent or dependent prognostic factor in glioma patients, more biomarkers known to have an impact on patient survival should be incorporated into clinical trials.

Supplementary Material

Supplementary material is available at Glioma online (http://www.jglioma.com/).

Financial support and sponsorship

This research was financially supported by grants from National Natural Science Foundation of China (No. 81573459).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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

  [Table 1], [Table 2]


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