Table 1 Table of characteristics for studies included in this systematic review
Authors | Reference # | GRADE | Year of Initial Publication | Subjects (Samples) | Tissue | Main lab method | Statistical Method | Outcome | Survival data? | IDH status included | CpG Type | Number of CpG sites Interrogated | List of CpG sites Interrogated | CpG sites of interest (associated with outcome)a |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Yildiz et al. | [16] | Low | 2007 | 100 (100) | FFPE | BS, PR, PSQ | χ², K-M, log-rank test, Cox PH | OS, PFS | Yes | No | Islands | 4 islands | CpG1, CpG2, CpG3, and CpG4 | PFS: CpG3; none found significant for OS |
Everhard et al. | [14] | Moderate | 2009 | 78 (54 GBM) | Frozen | PSQ, Expression Analysis, PCR | Mann-Whitney test, hierarchical clustering | Expression | Yes | No | Sites, Regions | 68 | 1-87 | Correlated with expression: 27, 32, 73, 75, 79 and 80; Concordant with expression: 32-33, 72-83 |
Malley et al. | [17] | High | 2011 | 22 (41) | Xenograft | Luciferase assay, PSQ, RT-PCR | Unsupervised hierarchical clustering, Mann- | mRNA expression, luciferase | No | No | Island, Cluster | 96 | Entire MGMT CGI | 83, 86, 87, 89 |
Shah et al. | [18] | High | 2011 | 70 (gene expression=4 6, PFS=44, IHC=31) | Frozen | BS, PCR, IHC, MS-MLPA | 3R classification, Spearman's rank correlation | mRNA expression, protein expression, and PFS | Yes | No | Sites, regions | 97 | Entire MGMT CGI | PFS: 8,22,38c,73c,75- 78,80- 82c,86c,87,88,89c |
Bady et al. | [19] | Moderate | 2012 | 63 (59 GBM) | Frozen | BS, HM-450K, HM-27K | Univariate model and stepwise logistic model building | OS | Yes | Yes | Sites | 176 (14 in promoter) | 17-20, 22, 25, 31, 60-62, 64, 70, 84, 97 | 19, 25 |
Quillien et al. | [15] | Moderate | 2014 | 89 (89) | FFPE | PSQ | Cox - AUROC, KM, bootstrapping Harold-C index | OS, PFS | Yes | No | Sites | 16 | 74-83, 84-89 | 89, means of 84- 88, 85-89, and 74- 89 |
De Carlo et al. | [20] | Low | 2015 | 121 (121) | NA | PSQ | Uni and multivariate Cox regression | OS, PFS | Yes | No | Sites | 10 | 74-83 | 74-77, 79-83 |
Mur et al. | [21] | Very low | 2015 | 68 (68) | Frozen/PE | BS, MSP, qMSP, HM- 450K | PCA and unsupervised hierarchical clustering, K-M, log- rank test, Spearman's correlation coefficient, multivariable Cox PH | OS | Yes | Yes | Sites | 154 (25 in promoter) | 1-10, 13-27 | 25, 165 |
Chai et al. | [1] | Moderate | 2018 | 159 (82b,77b) | FFPE | RNA-seq, PSQ | Spearman's correlation analysis, ROC | mRNA expression, OS | Yes | Yes | Sites, Combination | 11 | 75-82 (cohort #1), 72- 78(cohort #2) | 76-79 and 74-78 |
Siller et al | [22] | Low | 2021 | 215 IDH wild type | FFPE | MSP, Sanger | K-M, Log-rank test, Cox regression models, Multiple proportional hazards models, Spearman and Pearson correlation coefficient testing | OS | Yes | Yes | Sites | 25 | 74–98 | 74–98 |
Caccese | [23] | High | 2022 | 591 IDH wild type | FFPE | PSQ | Mann–Whitney U test ,χ², K-M, Cox regression model | OS | Yes | Yes | Sites | 10 | 75–84 | 75–84 |
Leske et al. | [24] | Low | 2023 | 32 long term survivors and 25 short term survivors | FFPE/Frozen | BS, PCR, Sanger sequencing | Random Forest regressions, conditional Random Forest analysis | OS | Yes | Yes | Sites | 79 | CpG 23 (bp − 300) to the end of the CpG island (bp + 289), CpG sites (bp + 292, + 296, + 309 | 86 has the highest predictive value. 75, 77, 78, 84, 88, and 96 |
Buyuktepe et al. | [25] | Moderate | 2023 | 95 (34 IDH wildtype) | FFPE | NGS, BS, MS- PCR, MS-HRM | Shapiro-Wilk test, t- test/Mann Whitney U, χ²/Fisher's exact test, K-M, Cox -ratio hazard model | OS/PFS | Yes | Yes | Islands/ whole promoter | 32 and whole promoter | CpG 70–78, CpG 79–83, CpG 84–87, CpG 70–87, and whole promoter | OS and PFS: CpG 79–83 and CpG 84–87 |
Gibson et al. | [26] | Low | 2023 | 300 (5 IDH mutant) | FFPE | MSP, CLIA based assay and BS | Cox proportional hazard,χ² | OS/PFS | Yes | Yes | Sites | 17 | 21-37 | medium levels of promoter methylation had greatest reduction in HR |
Zappe et al. | [27] | Low | 2023 | 40 GBM (1 IDH mutant, 1 gliosarcoma) | FFPE/T98G cell line | PCR, HRM, PSQ | One-way ANOVA followed by a post hoc t-test, K-M, scatter plot and Pearson's correlation coefficient | OS/MGMT protein level | Yes | Yes | Sites/Enhancer regions | 61 | CpG: 72-83, 4 enhancer regions | promoter: 75,78,80. enhancer region: low methylation of 01–03 and 09–13 |