Correlation of commercially available quantitative MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival

Laura Dovek, Nhung T. Nguyen, Byram Ozer, Ning Li, Robert M. Elashoff, Richard M. Green, Linda Liau, P. Leia Nghiemphu, Timothy F. Cloughesy, Albert Lai

Research output: Contribution to journalReview article

Abstract

Background. Between 2011 and 2016, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation testing at University of California Los Angeles (UCLA) was performed through LabCorp, using a threshold of 2 to distinguish MGMT methylated from unmethylated tumors. In this study, we sought to determine whether the magnitude of the methylation score correlated with outcome. Methods. We identified 165 newly diagnosed glioblastoma (GBM) isocitrate dehydrogenase (IDH) wild-type and temozolomide-treated upfront patients at UCLA and Kaiser Permanente Los Angeles with LabCorp-derived quantitative MGMT scores obtained on pretreatment tissue samples. Using LabCorp's threshold, we found 102 unmethylated and 63 methylated patients. We then further substratified each group based on the magnitude of the score, and performed Kaplan-Meier and Cox regression analyses of overall survival (OS) and progression-free survival (PFS). Results. We validated that the standard LabCorp threshold of 2 could separate our cohort by survival, showing longer OS and PFS for MGMT methylated patients vs unmethylated patients. Cox regression analysis confirmed that MGMT (<1) patients had worse outcome, with OS and PFS hazard ratios of 2.375 (P = .053) and 2.463 (P = .023), respectively, when compared to the MGMT (1-1.99) patients. Contrary to our expectation, when we substratified the ≥2 (methylated) group, we did not find a dose-dependent relationship between the magnitude of MGMT methylation and improved survival. Conclusions. The MGMT unmethylated group contains a partially methylated group (greater than 1) that shares survival benefits similar to the methylated group. However, we did not demonstrate an association of very high methylation scores with increased survival.These findings will require validation in additional independent clinical data sets.

Original languageEnglish (US)
Pages (from-to)194-202
Number of pages9
JournalNeuro-Oncology Practice
Volume6
Issue number3
DOIs
StatePublished - Jun 1 2019

Fingerprint

O(6)-Methylguanine-DNA Methyltransferase
Glioblastoma
Methylation
Survival
Los Angeles
Disease-Free Survival
temozolomide
Regression Analysis
Isocitrate Dehydrogenase
DNA Methylation

Keywords

  • Glioblastoma
  • Glioma
  • MGMT
  • Promoter methylation
  • Temozolomide

ASJC Scopus subject areas

  • Medicine (miscellaneous)

Cite this

Correlation of commercially available quantitative MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival. / Dovek, Laura; Nguyen, Nhung T.; Ozer, Byram; Li, Ning; Elashoff, Robert M.; Green, Richard M.; Liau, Linda; Leia Nghiemphu, P.; Cloughesy, Timothy F.; Lai, Albert.

In: Neuro-Oncology Practice, Vol. 6, No. 3, 01.06.2019, p. 194-202.

Research output: Contribution to journalReview article

Dovek, L, Nguyen, NT, Ozer, B, Li, N, Elashoff, RM, Green, RM, Liau, L, Leia Nghiemphu, P, Cloughesy, TF & Lai, A 2019, 'Correlation of commercially available quantitative MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival', Neuro-Oncology Practice, vol. 6, no. 3, pp. 194-202. https://doi.org/10.1093/nop/npy028
Dovek, Laura ; Nguyen, Nhung T. ; Ozer, Byram ; Li, Ning ; Elashoff, Robert M. ; Green, Richard M. ; Liau, Linda ; Leia Nghiemphu, P. ; Cloughesy, Timothy F. ; Lai, Albert. / Correlation of commercially available quantitative MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival. In: Neuro-Oncology Practice. 2019 ; Vol. 6, No. 3. pp. 194-202.
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title = "Correlation of commercially available quantitative MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival",
abstract = "Background. Between 2011 and 2016, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation testing at University of California Los Angeles (UCLA) was performed through LabCorp, using a threshold of 2 to distinguish MGMT methylated from unmethylated tumors. In this study, we sought to determine whether the magnitude of the methylation score correlated with outcome. Methods. We identified 165 newly diagnosed glioblastoma (GBM) isocitrate dehydrogenase (IDH) wild-type and temozolomide-treated upfront patients at UCLA and Kaiser Permanente Los Angeles with LabCorp-derived quantitative MGMT scores obtained on pretreatment tissue samples. Using LabCorp's threshold, we found 102 unmethylated and 63 methylated patients. We then further substratified each group based on the magnitude of the score, and performed Kaplan-Meier and Cox regression analyses of overall survival (OS) and progression-free survival (PFS). Results. We validated that the standard LabCorp threshold of 2 could separate our cohort by survival, showing longer OS and PFS for MGMT methylated patients vs unmethylated patients. Cox regression analysis confirmed that MGMT (<1) patients had worse outcome, with OS and PFS hazard ratios of 2.375 (P = .053) and 2.463 (P = .023), respectively, when compared to the MGMT (1-1.99) patients. Contrary to our expectation, when we substratified the ≥2 (methylated) group, we did not find a dose-dependent relationship between the magnitude of MGMT methylation and improved survival. Conclusions. The MGMT unmethylated group contains a partially methylated group (greater than 1) that shares survival benefits similar to the methylated group. However, we did not demonstrate an association of very high methylation scores with increased survival.These findings will require validation in additional independent clinical data sets.",
keywords = "Glioblastoma, Glioma, MGMT, Promoter methylation, Temozolomide",
author = "Laura Dovek and Nguyen, {Nhung T.} and Byram Ozer and Ning Li and Elashoff, {Robert M.} and Green, {Richard M.} and Linda Liau and {Leia Nghiemphu}, P. and Cloughesy, {Timothy F.} and Albert Lai",
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T1 - Correlation of commercially available quantitative MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival

AU - Dovek, Laura

AU - Nguyen, Nhung T.

AU - Ozer, Byram

AU - Li, Ning

AU - Elashoff, Robert M.

AU - Green, Richard M.

AU - Liau, Linda

AU - Leia Nghiemphu, P.

AU - Cloughesy, Timothy F.

AU - Lai, Albert

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background. Between 2011 and 2016, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation testing at University of California Los Angeles (UCLA) was performed through LabCorp, using a threshold of 2 to distinguish MGMT methylated from unmethylated tumors. In this study, we sought to determine whether the magnitude of the methylation score correlated with outcome. Methods. We identified 165 newly diagnosed glioblastoma (GBM) isocitrate dehydrogenase (IDH) wild-type and temozolomide-treated upfront patients at UCLA and Kaiser Permanente Los Angeles with LabCorp-derived quantitative MGMT scores obtained on pretreatment tissue samples. Using LabCorp's threshold, we found 102 unmethylated and 63 methylated patients. We then further substratified each group based on the magnitude of the score, and performed Kaplan-Meier and Cox regression analyses of overall survival (OS) and progression-free survival (PFS). Results. We validated that the standard LabCorp threshold of 2 could separate our cohort by survival, showing longer OS and PFS for MGMT methylated patients vs unmethylated patients. Cox regression analysis confirmed that MGMT (<1) patients had worse outcome, with OS and PFS hazard ratios of 2.375 (P = .053) and 2.463 (P = .023), respectively, when compared to the MGMT (1-1.99) patients. Contrary to our expectation, when we substratified the ≥2 (methylated) group, we did not find a dose-dependent relationship between the magnitude of MGMT methylation and improved survival. Conclusions. The MGMT unmethylated group contains a partially methylated group (greater than 1) that shares survival benefits similar to the methylated group. However, we did not demonstrate an association of very high methylation scores with increased survival.These findings will require validation in additional independent clinical data sets.

AB - Background. Between 2011 and 2016, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation testing at University of California Los Angeles (UCLA) was performed through LabCorp, using a threshold of 2 to distinguish MGMT methylated from unmethylated tumors. In this study, we sought to determine whether the magnitude of the methylation score correlated with outcome. Methods. We identified 165 newly diagnosed glioblastoma (GBM) isocitrate dehydrogenase (IDH) wild-type and temozolomide-treated upfront patients at UCLA and Kaiser Permanente Los Angeles with LabCorp-derived quantitative MGMT scores obtained on pretreatment tissue samples. Using LabCorp's threshold, we found 102 unmethylated and 63 methylated patients. We then further substratified each group based on the magnitude of the score, and performed Kaplan-Meier and Cox regression analyses of overall survival (OS) and progression-free survival (PFS). Results. We validated that the standard LabCorp threshold of 2 could separate our cohort by survival, showing longer OS and PFS for MGMT methylated patients vs unmethylated patients. Cox regression analysis confirmed that MGMT (<1) patients had worse outcome, with OS and PFS hazard ratios of 2.375 (P = .053) and 2.463 (P = .023), respectively, when compared to the MGMT (1-1.99) patients. Contrary to our expectation, when we substratified the ≥2 (methylated) group, we did not find a dose-dependent relationship between the magnitude of MGMT methylation and improved survival. Conclusions. The MGMT unmethylated group contains a partially methylated group (greater than 1) that shares survival benefits similar to the methylated group. However, we did not demonstrate an association of very high methylation scores with increased survival.These findings will require validation in additional independent clinical data sets.

KW - Glioblastoma

KW - Glioma

KW - MGMT

KW - Promoter methylation

KW - Temozolomide

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U2 - 10.1093/nop/npy028

DO - 10.1093/nop/npy028

M3 - Review article

C2 - 31386024

AN - SCOPUS:85067649183

VL - 6

SP - 194

EP - 202

JO - Neuro-Oncology Practice

JF - Neuro-Oncology Practice

SN - 2054-2577

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