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Open Access 01-12-2023 | Glioma | Research

Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results

Authors: Matthew McCord, Pouya Jamshidi, Vineeth Thirunavu, Lucas Santana-Santos, Erica Vormittag-Nocito, David Dittman, Stephanie Parker, Joseph Baczkowski, Lawrence Jennings, Jordain Walshon, Kathleen McCortney, Kristyn Galbraith, Hui Zhang, Rimas V. Lukas, Roger Stupp, Karan Dixit, Priya Kumthekar, Amy B. Heimberger, Matija Snuderl, Craig Horbinski

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellularity and identify possible false-negative MGMT samples. Among 691 adult-type diffuse gliomas, MGMT promoter methylation was assessed by pyrosequencing (N = 445) or DNA methylation array (N = 246); VAFs of TERT and IDH driver mutations were assessed by next generation sequencing. MGMT results were analyzed in relation to VAF. By pyrosequencing, 56% of all gliomas with driver mutation VAF ≥ 0.325 had MGMT promoter methylation, versus only 37% with VAF < 0.325 (p < 0.0001). The mean MGMT promoter pyrosequencing score was 19.3% for samples with VAF VAF ≥ 0.325, versus 12.7% for samples with VAF < 0.325 (p < 0.0001). Optimal VAF cutoffs differed among glioma subtypes (IDH wildtype glioblastoma: 0.12–0.18, IDH mutant astrocytoma: ~0.33, IDH mutant and 1p/19q co-deleted oligodendroglioma: 0.3–0.4). Methylation array was more sensitive for MGMT promoter methylation at lower VAFs than pyrosequencing. Microscopic examination tended to overestimate tumor cellularity when VAF was low. Re-testing low-VAF cases with methylation array and droplet digital PCR (ddPCR) confirmed that a subset of them had originally been false-negative. We conclude that driver mutation VAF is a useful quality assurance metric when evaluating MGMT promoter methylation tests, as it can help identify possible false-negative cases.

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Title: Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results
Authors: Matthew McCord
Pouya Jamshidi
Vineeth Thirunavu
Lucas Santana-Santos
Erica Vormittag-Nocito
David Dittman
Stephanie Parker
Joseph Baczkowski
Lawrence Jennings
Jordain Walshon
Kathleen McCortney
Kristyn Galbraith
Hui Zhang
Rimas V. Lukas
Roger Stupp
Karan Dixit
Priya Kumthekar
Amy B. Heimberger
Matija Snuderl
Craig Horbinski
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Glioma
Glioma
Glioma
Oligodendroglioma
Astrocytoma
Astrocytoma
Astrocytoma
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01680-0

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Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results

Abstract

Keynote webinar | Spotlight on medication adherence

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Abstract

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