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MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence
- Source :
- Neuro Oncol, Neuro-oncology, vol 22, iss 11
- Publication Year :
- 2020
-
Abstract
- Background Emerging data suggest that a subset of patients with diffuse isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG) who receive adjuvant temozolomide (TMZ) recur with hypermutation in association with malignant progression to higher-grade tumors. It is currently unclear why some TMZ-treated LGG patients recur with hypermutation while others do not. MGMT encodes O6-methylguanine-DNA methyltransferase, a DNA repair protein that removes cytotoxic and potentially mutagenic lesions induced by TMZ. Here, we hypothesize that epigenetic silencing of MGMT by promoter methylation facilitates TMZ-induced mutagenesis in LGG patients and contributes to development of hypermutation at recurrence. Methods We utilize a quantitative deep sequencing assay to characterize MGMT promoter methylation in 109 surgical tissue specimens from initial tumors and post-treatment recurrences of 37 TMZ-treated LGG patients. We utilize methylation arrays to validate our sequencing assay, RNA sequencing to assess the relationship between methylation and gene expression, and exome sequencing to determine hypermutation status. Results Methylation level at the MGMT promoter is significantly higher in initial tumors of patients that develop hypermutation at recurrence relative to initial tumors of patients that do not (45.7% vs 34.8%, P = 0.027). Methylation level in initial tumors can predict hypermutation at recurrence in univariate models and multivariate models that incorporate patient age and molecular subtype. Conclusions These findings reveal a mechanistic basis for observed differences in patient susceptibility to TMZ-driven hypermutation. Furthermore, they establish MGMT promoter methylation level as a potential biomarker to inform clinical management of LGG patients, including monitoring and treatment decisions, by predicting risk of hypermutation at recurrence.
- Subjects :
- Cancer Research
Methyltransferase
temozolomide
glioma
Promoter Regions, Genetic
DNA Modification Methylases
Exome sequencing
Cancer
Brain Neoplasms
Methylation
Glioma
Alkylating
Oncology
Local
Basic and Translational Investigations
biomarker
MGMT
medicine.drug
Oncology and Carcinogenesis
Somatic hypermutation
Antineoplastic Agents
Deep sequencing
Rare Diseases
Clinical Research
medicine
Genetics
Temozolomide
Humans
Oncology & Carcinogenesis
Antineoplastic Agents, Alkylating
business.industry
Tumor Suppressor Proteins
hypermutation
Human Genome
Neurosciences
Editorials
O-6-methylguanine-DNA methyltransferase
DNA Methylation
medicine.disease
Brain Disorders
Brain Cancer
Neoplasm Recurrence
DNA Repair Enzymes
Cancer research
Neurology (clinical)
Neoplasm Recurrence, Local
business
Subjects
Details
- ISSN :
- 15235866
- Volume :
- 22
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Neuro-oncology
- Accession number :
- edsair.doi.dedup.....adfe69826e351cf67c69d6c9f490113c