Abstract
Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies.
Highlights
O6-methylguanine DNA methyltransferase (MGMT) is the major clinically used predictive and prognostic biomarker of survival following RT and TMZ chemotherapy
Multiple spatially distinct biopsies were taken from the same glioblastoma tumor in order to investigate intratumoral heterogeneity in key glioma biomarkers including MGMT promoter methylation and transcriptional subtype
We examined whether tumors displayed intratumoral heterogeneity in the mismatch repair (MMR) and base excision repair (BER) DNA repair pathways which may promote intrinsic or acquired treatment resistance
Summary
O6-methylguanine DNA methyltransferase (MGMT) is the major clinically used predictive and prognostic biomarker of survival following RT and TMZ chemotherapy. Glioblastoma patients with methylated MGMT promoters have a more favorable outcome when treated with combination RT and TMZ versus RT alone[14]. Other cellular DNA repair mechanisms including the mismatch repair (MMR) and base excision repair (BER) pathways may contribute and intratumoral heterogeneity in these pathways would further confound results. The molecular subtype of the tumor can be used as a predictive biomarker of outcome and response to therapy. Multiple spatially distinct biopsies were taken from the same glioblastoma tumor in order to investigate intratumoral heterogeneity in key glioma biomarkers including MGMT promoter methylation and transcriptional subtype. We examined whether tumors displayed intratumoral heterogeneity in the MMR and BER DNA repair pathways which may promote intrinsic or acquired treatment resistance
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