|Year : 2020 | Volume
| Issue : 1 | Page : 1-8
No association between isocitrate dehydrogenase 1 mutation and increased survival of glioblastoma: A meta-analysis
Thara Tunthanathip1, Kantapong Mamueang2, Nichapat Nilbupha2, Chattarin Maliwan2, Tanan Bejrananda3
1 Department of Surgery, Division of Neurosurgery, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
2 Department of Medical Education, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
3 Department of Surgery, Division of Urology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
|Date of Submission||26-Nov-2019|
|Date of Decision||29-Feb-2020|
|Date of Acceptance||06-May-2020|
|Date of Web Publication||20-Jul-2020|
Dr. Thara Tunthanathip
Department of Surgery, Division of Neurosurgery, Faculty of Medicine, Prince of Songkla University, Songkhla 90110
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: To systematically examine the prognostic significance of isocitrate dehydrogenase 1 (IDH1) mutations according to country region. Methods: We searched five electronic databases from inception to September 2019 for relevant studies. A meta-analysis was performed after evaluating which studies met the inclusion criteria. Thirty-seven were identified for this meta-analysis, comprising 5141 GBM patients. Results: The benefit of overall survival (OS) was the hazard ratio (HR), 0.67 (95% confidence interval [CI], 0.61–0.74). When subgroup analysis by country region, the pooled HR for the Eastern population studies was 1.15 (95% CI: 0.97–1.35) with no association between IDH1 mutation and OS of GBM, while IDH1 mutation still had a significant survival advantage in the Western population studies (HR: 0.51, 95% CI: 0.45–0.57). Conclusions: This study confirmed that IDH1 mutation is an independent prognostic factor for patients with GBM. However, a topographic relationship was observed in the results, and an association between this genetic mutation and prognosis should be explored in future studies.
Keywords: Glioblastoma, isocitrate dehydrogenase 1, meta-analysis, survival, systematic review
|How to cite this article:|
Tunthanathip T, Mamueang K, Nilbupha N, Maliwan C, Bejrananda T. No association between isocitrate dehydrogenase 1 mutation and increased survival of glioblastoma: A meta-analysis. J Pharm Negative Results 2020;11:1-8
|How to cite this URL:|
Tunthanathip T, Mamueang K, Nilbupha N, Maliwan C, Bejrananda T. No association between isocitrate dehydrogenase 1 mutation and increased survival of glioblastoma: A meta-analysis. J Pharm Negative Results [serial online] 2020 [cited 2020 Aug 11];11:1-8. Available from: http://www.pnrjournal.com/text.asp?2020/11/1/1/290204
| Introduction|| |
Glioblastoma (GBM) is classified as a Grade IV glioma by the World Health Organization (WHO), which is the mortal primary malignant brain tumor in adults. A median overall survival (OS) of GBM has been reported in the range of 12.1–14.6 months. In 2016, the WHO revised the classification of glioma, including GBM based on isocitrate dehydrogenase (IDH) gene mutation. Mutation of IDH1 has been described to be pathophysiology of glioma and malignant transformation in secondary GBM in comprehensive studies. Patients with mutant-IDH1GBM have a better prognosis than wild-type IDH1 GBM.,
Peasons et al. reported that the median survival time of patients with mutant IDH1 GBM was 3.8 years compared with 1.1 years of patients with wild-type IDH1 GBM (log-rank test, P < 0.001). Therefore, several studies demonstrated that patients with a GBM carrying an IDH1 mutation had survival time significantly longer than patients with wild-type IDH1.,,
However, the proportion of IDH1 mutation has been reported in the range of 6%–10% of all GBM.,, Therefore, this biomarker has been debated in the role of a predictor for prognosis. In studies from China, Wang studied the prognostic factors in 234 patients with GBM, patients with mutant IDH1 GBM did not survive longer than patients with wild-type GBM (log-rank test, P = 0.488), and Yang et al. studied the protein expression of CD 147 in Chinese patients with GBM. The results in the multivariable analysis showed that IDH1 mutation was not associated with survival (hazard ratio [HR]: 1.46, 95% confidence interval [CI] = 0.96–2.27). Moreover, the results of Uno et al. in 161 Brazilian patients with GBM showed that mutant IDH1 GBM was not significantly associated with longer survival than wild-type IDH1 GBM (log-rank test, P = 0.075).
From this inconclusive topic, we systematically examined the prognostic significance of IDH1 mutations and comparatively assessed between Eastern and Western studies.
| Methods|| |
This study was reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline recommendations. PubMed, the Cochrane Library, Web of Science, EMBASE, and Google Scholar databases were searched from inception to September 30, 2019.
The following search term used: “Glioblastoma multiforme” OR “Glioblastoma” OR “GBM” OR “High-grade glioma” AND “isocitrate dehydrogenase” OR “isocitrate dehydrogenases 1” OR “IDH1”. Publications were limited to human research published in English. Three investigators (K.M., N.N., C.M.) independently assessed the titles and abstracts retrieved by the search strategy for potential eligibility. Any disagreements were resolved through discussion until a consensus was reached.
Selection criteria and abstract screening
Search publications were imported into the web-based application Rayyan and duplicates were deleted. Titles and abstracts of included studies were blind-on screened by two authors (T.T. and T.B.).
The inclusion criteria were as follows: (I) to deal with GBM only; (II) to evaluate the association between IDH1 mutation and patient survival; (III) to be published as a full paper in English language literature; and (IV) to provide sufficient information, such as the Kaplan–Meier curve, the HR, and 95% CI for OS.
Full-text screening and data extraction
Two authors (T.T. and T.B.) independently read the full-text for screening. The data extractions were independently performed by two authors. Any disagreements were discussed and resolved by consensus. The following information was retrieved: authors, publication year, Country, number of patients, and IDH1 mutation. In addition, we used OS as the endpoint.
Quality score assessment
Using the Newcastle–Ottawa Scale (NOS), the two review authors (T.T. and T.B.) independently assessed the quality of studies that met the inclusion criteria, with disagreement resolved by consensus. The two authors independently awarded stars for studies (maximum of nine stars) based on a developed checklist. Moderate to high-quality studies, which studies gave at least six stars, were included in analysis. Moreover, studies with less than six stars were defined as low-quality studies and excluded from the meta-analysis.
By Tierney et al., the difference between numbers of observed and expected events (O-E) and the variance (V) was calculated when studies reported HRs and 95% CI. However, Generating the O-E and V from Kaplan–Meier curves was performed when HRs were unavailable.
The individual HR estimates were combined into a pooled HR for OS using the random-model effect weighted by the inverse variance method. An HR of more than 1 indicated a compromised prognosis in GBM patients with wild-type IDH1. Therefore, we assessed the subgroup analysis, such as year of publication and region (Eastern and Western countries).
The heterogeneity among studies was determined with the I2 statistic, which with values, more than 50% indicates visible heterogeneity. Moreover, a visual inspection of the funnel plot was performed to evaluate publication bias.
Survival rates on the graphical illustration of the Kaplan–Meier curves were extracted by Plot Digitizer Version 2.6.8. The pooled HRs and 95% CI were calculated by Review Manager 5.3 software (Cochrane Collaborative, Oxford, UK).
| Results|| |
Characteristics of included studies
The literature search identified a total of 3250 studies, as shown in [Figure 1]. After the removal of 235 duplicated studies, inclusion and exclusion criteria were applied to titles and abstracts of the 3015 articles. Two thousand nine hundred sixty-four studies were removed after the title and abstract screening. The full-text analysis was performed on 60 studies. Consequently, 51 studies were included in qualitative synthesis, and 12 studies were excluded because of unextractable survival data. Therefore, the authors evaluated the quality of the 39 papers, using the NOS criteria. Finally, two studies were removed because of a NOS score of less than 6. The remaining 37 studies with scores ranging from 7 to 9 were included in the quantitative synthesis. Hence, the summarized characteristics of 37 studies are demonstrated in [Table 1], and lists of studied included in quantitative synthesis are shown in Supplement.
|Figure 1: Preferred reporting items for systematic reviews and metaanalyses flow diagram|
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|Table 1: Characteristics of 37 included studies and survival data the prognostic impacts of isocitrate dehydrogenase 1 mutation in Glioblastoma multiforme patients|
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There were 37 studies with a total of 5141 patients focused on the relationship between IDH1 mutation and OS of GBM, as shown in [Figure 2]. When compared to wild-type IDH1, patients with mutant IDH1 significantly prolonged OS (HR: 0.67, 95% CI: 0.61–0.74, I2 86%). However, there was evidence of heterogeneity for OS (I2 86%). Further subgroup analysis by the country and region of the studies and the year of publication were performed. Subgroup analyses showed that the I2 value declined in the papers published before 2011 (I2 5%). Patients with mutant IDH1 still had significantly prolonger OS than patients with wild-type IDH1, as shown in [Figure 3]a and [Figure 3]b.
|Figure 3: Forest plot of publications according to (a) Western and (b) Eastern studies|
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For subgroup analysis by Country regions, we observed that there were no statistically significant differences in OS between mutant IDH1 and wild-type IDH1 groups in the Eastern studies (HR: 1.15, 95% CI: 0.97–1.35, I2 82%). In Western studies, the IDH1 mutation also demonstrated superior OS benefit compared with wild-type IDH1 (HR 0.51, 95% CI: 0.45–0.57, I2 81%), as shown in [Figure 4]a and [Figure 4]b. In addition, the heterogeneity diminished in the Eastern studies published before 2013 (HR: 1.21, 95% CI: 0.99–1.49, I2 63%) with the same result.
|Figure 4: Forest plot of publications according to (a) 2009–2010 and (b) 2011–2016 periods|
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Results of sensitivity analysis
When removal of the eight studies that had NOS scores of less than eight was performed, patients with mutant IDH1 still had significantly prolonged OS than patients with wild-type IDH1 (HR: 0.67, 95% CI: 0.60–0.74). Likewise, there was a significant difference in the pooled HRs of the association between the IDH1 and OS of GBM (HR: 0.67, 95% CI: 0.59–0.76) when the sixteen studies generated the O-E and V from Kaplan–Meier curves were removed.
The funnel plots seem symmetrical in all publications and subgroup analyses that demonstrated no substantial publication bias, as shown in [Figure 5]a, [Figure 5]b, [Figure 5]e.
|Figure 5: Funnel plot of (a) all publications, (b) Western studies, (c) Eastern studies, (d) 2009–2010 periods, and (e) 2011–2016 periods|
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| Discussion|| |
IDH1 mutations occur approximately 10% of GBM from the literature. IDH1 mutation has been reported as the biomarker strongly associated with survival time. From the Cancer Genome Atlas Research Network study, mutations in IDH have been concerned as clinically related biomarkers of gliomas. Moreover, Yan et al. studied the association between a mutation in IDH1 and reported that patients with mutant IDH1 had significantly longer OS over than patients with wild-type IDH1. Hence, GBM is classified by this genetic mutation in the current. However, no association of IDH1 has been observed in subsequent prior studies. Amelot et al. studied in 207 GBM patients and reported that IDH1 mutation was weak at predicting prognosis of GBM patients. Moreover, Hartmann et al. studied long-term survival in a patient with GBM and found that the mutation of IDH1 was not significantly associated with prognosis from the survival curves. In the present study, our pooled results from meta-analysis demonstrated that patients with mutant IDH1 mutant GBM had a significant OS advantage than IDH1 wild-type GBM.
Compared with the meta-analysis published in 2013, IDH1 mutation in GBM patients was associated with a favorable prognosis (HR 0.45, 95% CI: 0.29–0.69). High heterogeneity was observed in the present results; therefore, the problem resolved when subgroup analysis was performed by periods of studies. The results of the subgroup analysis were in concordance with the results from prior publications.
IDH1 mutation leads to reducing the α-Ketoglutarate (α-KG) level and increasing the D-2-hydroxyglutarate (2-HG) level. The α-KG is a principle cofactor for DNA and histone demethylation, whereas 2-HG is a competitive inhibitor. The subsequent accumulation of 2-HG results in epigenetic dysregulation via inhibition of α-KG-dependent histone and DHA demethylases.,, These mechanisms link to a survival benefit in patients with mutant IDH1 GBM.
However, the present meta-analysis additionally established the country of studies affected the results. The pooled HR of IDH1 mutation was not significant in the Eastern subgroup, including China, Japan, Korea, and India. Topographic linkage considered in the different associations between these genetic mutations and prognosis should be explored in future studies. The other hypothesis is the further biomarkers may be more potential than IDH1 mutation in each topographical environment, such as O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and the telomerase reverse transcriptase promoter (TERTp) mutation. Both genetic alterations are more commonly found than the IDH1 mutation.
MGMT promoter methylation has been reported in 33%–95% of GBM, and the methylation regulates this protein. In unmethylated MGMT promoter, The MGMT protein rapidly alters structures of the alkylated agent. Through this process, MGMT protein causes resistance to alkylating drugs. The methylation of the promoter region of the MGMT gene leads to prevent MGMT protein expression; therefore, a lack of MGMT enzyme increases the sensitivity of brain tumors to alkylating agents. GBM patients with MGMT promoter methylation response to combined treatment with radiotherapy and temozolomide had a prolonged OS, unmethylated MGMT promoter in meta-analysis studies.,,
Additionally, TERTp mutations were found to range between 76.9 and 84.6% in GBM and have been associated with a worse prognosis. These mutations, cytidine-to-thymidine transitions at sites 1,295,228 (C228T), and 1,295,250 (C250T) on chromosome 5 dysregulate the normal catalytic subunit of the telomerase. Therefore, the lifecycle of the cellular telomerase unit is lengthy, enhancing cellular prolongation and self-renewal that is associated with poor prognosis in GBM patients. Both biomarkers should be explored according to topography in the future.
In the present study, no association of IDH1 mutation was observed from the Eastern studies, but, high heterogeneity was observed. The following may be explained by the different years of publication. The I2 value declined in publications before 2013, whereas the same results were observed for the association between IDH1 mutation and prognosis of GBM patients. Limitations of the present study should be acknowledged that a lack of data of treatment, mainly the extent of resection and chemotherapy, was limited in the present study.
| Conclusions|| |
This study confirmed that IDH1 mutation is an independent prognostic factor for patients with GBM. However, the topographic relationship was observed in the results, and the association between this genetic mutation and prognosis should be explored in future studies.
The authors would like to offer their special thanks to Professor. Tippawan Liabsuetrakul and Assoc. Prof. Dr. Paramee Thongsukhsaifor advice about meta-analysis and manuscript preparation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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