Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

Abstract

Promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is a critical biomarker in glioblastoma (GBM), as treatment decisions and clinical trial inclusion rely on its accurate assessment. However, interpretation of results is complicated by poor interassay reproducibility as well as a weak correlation between methylation status and expression levels of MGMT. This study systematically investigates the influence of tumor purity on tissue subjected to MGMT analysis. A quantitative, allele-specific realtime PCR (qAS-PCR) assay was developed to determine genotype and mutant allele frequency of telomerase promoter (pTERT) mutations as a direct measure of tumor purity. We studied tumor purity, pTERT mutation by Sanger sequencing, MGMT methylation by pyrosequencing, IDH1 mutation status, and clinical parameters in a cohort of high-grade gliomas (n ¼ 97). The qAS-PCR reliably predicted pTERT genotype and tumor purity compared with independent methods. Tumor purity positively and significantly correlated with the extent of methylation in MGMT methylated GBMs. Extent of MGMT methylation differed significantly with respect to pTERT mutation hotspot (C228T vs. C250T). Interestingly, frontal lobe tumors showed greater tumor purity than those in other locations. Above all, tumor purity was identified as an independent prognostic factor in GBM. In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532-40. Ó2017 AACR.

Integrating Genomic Data with Transcriptomic Data for Improved Survival Prediction for Adult Diffuse Glioma

“…For all pathological variables, histology demonstrated the highest importance in LGGs, and purity index for GBMs. Our results indicated that glioma purity has great value in predicting the prognosis, which was also pointed out by other researchers [24][25][26] but is not widely used.…”

ADAMTSL4, a Secreted Glycoprotein, Is a Novel Immune-Related Biomarker for Primary Glioblastoma Multiforme

“…The tumor microenvironment does not only include tumor cells but also infiltrated immune cells, fibroblasts, and stromal cells comprising the tumor volume [35]. Several studies suggested that lower tumor purity is frequently linked to aggressive characteristics [26, 36]. In this study, we found that both the immune and stromal scores were positively correlated to the ADAMTSL4 expression, suggesting that ADAMTSL4 could reflect the increased fraction of immune and stromal cells.…”

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

“…This was clearly shown by Patel and colleagues who demonstrated that pure IDH1 wild-type proneural tumors were associated with a better survival compared to highly heterogeneous proneural tumors containing cells with other subtypes [21]. Similarly, tumor purity was recently shown to be an important parameter to determine a positive association of MGMT methylation with patient survival [17]. We show that ZBTB18 attenuates the expression of genes associated with EMT and with time-to-tumor progression in glioblastoma [36, 37].…”

“…The DNA repair gene O-6-methylguanine-DNA methyltransferase ( MGMT ) is one such gene for which promoter methylation has been shown to result in gene silencing in many cancers [15-17]. …”