Association between small heat shock protein B11 and the prognostic value of MGMT promoter methylation in patients with high-grade glioma

Abstract

G lioma is the most common type of tumor in the CNS. The WHO classifies glioma on a scale of Grades I-IV, according to histopathologic features. 28 Grades III and IV are progressive, resistant to treatment, and grouped together as high-grade glioma (HGG) for the purposes of clinical management. Glioblastoma and anaplastic glioma comprise the majority of HGG cases. Since the incorporation of alkylating agents such as temozolomide (TMZ) into routine chemotherapy, the prognosis for patients with HGG has significantly improved. The epigenetic silencing of O 6 -methylguanine-DNA methyltransferase (MGMT) (which encodes a DNA repair protein) by promoter methylation is associated with favorable prognosis in patients with HGG. 35,40,41 Numerous studies have also shown that MGMT promoter methylation can be used to predict the extent to which patients abbreviatioNs CGGA = Chinese Glioma Genome Atlas; GBM = glioblastoma; GO = gene ontology; GSEA = Gene Set Enrichment Analysis; HGG = high-grade glioma; HSP = heat shock protein; IDH1 = isocitrate dehydrogenase 1; KPS = Karnofsky Performance Scale; LGG = low-grade glioma; MGMT = O 6 -methylguanine-DNA methyltransferase; mRNA = messenger RNA; OS = overall survival; PCR = polymerase chain reaction; PFS = progression-free survival; REMBRANDT = Repository for Molecular Brain Neoplasia Data; SAM = significance analysis of microarrays; TMZ = temozolomide. results Of 28 HSPs, 11 were overexpressed in high-grade glioma (HGG) compared with low-grade glioma. A univariate Cox analysis revealed that HSPB11 has significant prognostic value for each glioma grade, which was validated by a Kaplan-Meier survival analysis. HSPB11 expression was associated with poor prognosis and was independently correlated with overall survival (OS) in HGG. This study further explored the combined role of HSPB11 and other molecular markers in HGG, such as isocitrate dehydrogenase 1 (IDH1) mutation and O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation status. HSPB11 expression was able to refine the prognostic value of IDH1 mutation in patients with HGG. However, when combined with MGMT promoter methylation status, among patients with a methylated MGMT promoter, those with lower levels of HSPB11 expression had longer OS and progression-free survival than patients with higher levels of HSPB11 expression or with an unmethylated MGMT promoter. Moreover, within the MGMT promoter methylation group, patients with low levels of HSPB11 expression were more sensitive to combined radiochemotherapy than those with high levels of HSPB11 expression, which may explain why some patients with HGG with a methylated MGMT promoter show tolerance to radiochemotherapy. coNclusioNs HSPB11 was identified as a novel prognostic marker in patients with HGG. Together with MGMT promoter methylation status, HSPB11 expression can predict outcome for patients with HGG and identify those who would most benefit from combined radiochemotherapy.

Costimulatory checkpoint SLAMF8 is an independent prognosis factor in glioma

“…Overall survival (OS) was estimated from date of diagnosis to death or final follow‐up. Methods for sequencing, detecting IDH mutation, and MGMT promoter methylation state were described previously …”

“…Methods for sequencing, detecting IDH mutation, and MGMT promoter methylation state were described previously. 18,19…”

<p>IFI30 Is a Novel Immune-Related Target with Predicting Value of Prognosis and Treatment Response in Glioblastoma</p>

“…Methods for sequencing, MGMT promoter methylation and isocitrate dehydrogenase (IDH) mutation state were mentioned earlier. 11,12 The normalization was conducted by log2 transformed after adding a 0.5 pseudocount based on the pre-processed data.…”

Combinations of four or more CpGs methylation present equivalent predictive value for MGMT expression and temozolomide therapeutic prognosis in gliomas

“…However, along with the high heterogeneity of the CpGs methylation gradually identified, MSP‐based methods were unable to reflect such heterogeneity . Currently, pyrosequencing (PSQ) has been developed to be a stable technique, offering a valid, reliable and quick evaluation of both fresh frozen and formalin fixed paraffin embedded (FFPE) specimens …”

“…12,15,16 Currently, pyrosequencing (PSQ) has been developed to be a stable technique, offering a valid, reliable and quick evaluation of both fresh frozen and formalin fixed paraffin embedded (FFPE) specimens. 11,13,14,[17][18][19][20][21][22] Similar to the MSP method, PSQ determines the MGMT promoter methylation by the mean methylation level of several selected consecutive CpGs. 11,15,23 The methylation statuses of CpGs and 72-90 are proved highly correlated to MGMT transcription, and CpGs 72-90 seems to play a more critical role.…”