Preferential MGMT hypermethylation in SDH-deficient wild-type GIST

Olivier T Giger; Rogier Ten Hoopen; David Shorthouse; Shukri Abdullahi; Venkata Ramesh Bulusu; Saili Jadhav; Eamonn R Maher; Ruth T Casey

doi:10.1136/jcp-2022-208462

Preferential MGMT hypermethylation in SDH-deficient wild-type GIST

Olivier T Giger, Rogier Ten Hoopen, David Shorthouse, Shukri Abdullahi, Venkata Ramesh Bulusu, Saili Jadhav, Eamonn R Maher, Ruth T Casey

Research output: Contribution to journal › Article › peer-review

Abstract

AIMS: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (SDHx). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by SDHx inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation. Epigenetic silencing of the DNA repair gene MGMT has proven utility as a positive predictor of the therapeutic efficacy of the alklyating drug temozolomide (TMZ) in tumours such as glioblastoma multiforme. The aim of this study was to examine MGMT promoter methylation status in a large cohort of GIST.

METHODS: MGMT methylation analysis was performed on 65 tumour samples including 47 wtGIST (33 SDH-deficient wtGIST and 11 SDH preserved wtGIST) and 21 tyrosine kinase (TK) mutant GIST.

RESULTS: MGMT promoter methylation was detected in 8 cases of SDH-deficient (dSDH) GIST but in none of the 14 SDH preserved wild-type GIST or 21 TK mutant GIST samples analysed. Mean MGMT methylation was significantly higher (p 0.0449) and MGMT expression significantly lower (p<0.0001) in dSDH wtGIST compared with TK mutant or SDH preserved GIST. No correlation was identified between SDHx subunit gene mutations or SDHC epimutation status and mean MGMT methylation levels.

CONCLUSION: MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy.

Original language	English
Pages (from-to)	34-39
Number of pages	6
Journal	Journal of Clinical Pathology
Volume	77
Issue number	1
Early online date	5 Oct 2022
DOIs	https://doi.org/10.1136/jcp-2022-208462
Publication status	Published - 14 Dec 2023

Bibliographical note

© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

Keywords

Humans
Succinate Dehydrogenase
Gastrointestinal Stromal Tumors/genetics
DNA Methylation
Epigenesis, Genetic
Mutation
Protein-Tyrosine Kinases/genetics
DNA Repair Enzymes/genetics
DNA Modification Methylases/genetics
Tumor Suppressor Proteins/genetics

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Cite this

@article{7f282613a0454159a465ee34bf904385,

title = "Preferential MGMT hypermethylation in SDH-deficient wild-type GIST",

abstract = "AIMS: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (SDHx). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by SDHx inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation. Epigenetic silencing of the DNA repair gene MGMT has proven utility as a positive predictor of the therapeutic efficacy of the alklyating drug temozolomide (TMZ) in tumours such as glioblastoma multiforme. The aim of this study was to examine MGMT promoter methylation status in a large cohort of GIST.METHODS: MGMT methylation analysis was performed on 65 tumour samples including 47 wtGIST (33 SDH-deficient wtGIST and 11 SDH preserved wtGIST) and 21 tyrosine kinase (TK) mutant GIST.RESULTS: MGMT promoter methylation was detected in 8 cases of SDH-deficient (dSDH) GIST but in none of the 14 SDH preserved wild-type GIST or 21 TK mutant GIST samples analysed. Mean MGMT methylation was significantly higher (p 0.0449) and MGMT expression significantly lower (p<0.0001) in dSDH wtGIST compared with TK mutant or SDH preserved GIST. No correlation was identified between SDHx subunit gene mutations or SDHC epimutation status and mean MGMT methylation levels.CONCLUSION: MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy.",

keywords = "Humans, Succinate Dehydrogenase, Gastrointestinal Stromal Tumors/genetics, DNA Methylation, Epigenesis, Genetic, Mutation, Protein-Tyrosine Kinases/genetics, DNA Repair Enzymes/genetics, DNA Modification Methylases/genetics, Tumor Suppressor Proteins/genetics",

author = "Giger, {Olivier T} and {Ten Hoopen}, Rogier and David Shorthouse and Shukri Abdullahi and Bulusu, {Venkata Ramesh} and Saili Jadhav and Maher, {Eamonn R} and Casey, {Ruth T}",

note = "{\textcopyright} Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.",

year = "2023",

month = dec,

day = "14",

doi = "10.1136/jcp-2022-208462",

language = "English",

volume = "77",

pages = "34--39",

journal = "Journal of Clinical Pathology ",

issn = "0021-9746",

publisher = "BMJ Publishing Group",

number = "1",

}

TY - JOUR

T1 - Preferential MGMT hypermethylation in SDH-deficient wild-type GIST

AU - Giger, Olivier T

AU - Ten Hoopen, Rogier

AU - Shorthouse, David

AU - Abdullahi, Shukri

AU - Bulusu, Venkata Ramesh

AU - Jadhav, Saili

AU - Maher, Eamonn R

AU - Casey, Ruth T

N1 - © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

PY - 2023/12/14

Y1 - 2023/12/14

N2 - AIMS: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (SDHx). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by SDHx inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation. Epigenetic silencing of the DNA repair gene MGMT has proven utility as a positive predictor of the therapeutic efficacy of the alklyating drug temozolomide (TMZ) in tumours such as glioblastoma multiforme. The aim of this study was to examine MGMT promoter methylation status in a large cohort of GIST.METHODS: MGMT methylation analysis was performed on 65 tumour samples including 47 wtGIST (33 SDH-deficient wtGIST and 11 SDH preserved wtGIST) and 21 tyrosine kinase (TK) mutant GIST.RESULTS: MGMT promoter methylation was detected in 8 cases of SDH-deficient (dSDH) GIST but in none of the 14 SDH preserved wild-type GIST or 21 TK mutant GIST samples analysed. Mean MGMT methylation was significantly higher (p 0.0449) and MGMT expression significantly lower (p<0.0001) in dSDH wtGIST compared with TK mutant or SDH preserved GIST. No correlation was identified between SDHx subunit gene mutations or SDHC epimutation status and mean MGMT methylation levels.CONCLUSION: MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy.

AB - AIMS: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (SDHx). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by SDHx inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation. Epigenetic silencing of the DNA repair gene MGMT has proven utility as a positive predictor of the therapeutic efficacy of the alklyating drug temozolomide (TMZ) in tumours such as glioblastoma multiforme. The aim of this study was to examine MGMT promoter methylation status in a large cohort of GIST.METHODS: MGMT methylation analysis was performed on 65 tumour samples including 47 wtGIST (33 SDH-deficient wtGIST and 11 SDH preserved wtGIST) and 21 tyrosine kinase (TK) mutant GIST.RESULTS: MGMT promoter methylation was detected in 8 cases of SDH-deficient (dSDH) GIST but in none of the 14 SDH preserved wild-type GIST or 21 TK mutant GIST samples analysed. Mean MGMT methylation was significantly higher (p 0.0449) and MGMT expression significantly lower (p<0.0001) in dSDH wtGIST compared with TK mutant or SDH preserved GIST. No correlation was identified between SDHx subunit gene mutations or SDHC epimutation status and mean MGMT methylation levels.CONCLUSION: MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy.

KW - Humans

KW - Succinate Dehydrogenase

KW - Gastrointestinal Stromal Tumors/genetics

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Mutation

KW - Protein-Tyrosine Kinases/genetics

KW - DNA Repair Enzymes/genetics

KW - DNA Modification Methylases/genetics

KW - Tumor Suppressor Proteins/genetics

UR - https://jcp.bmj.com/content/77/1/34

UR - http://www.scopus.com/inward/record.url?scp=85142519982&partnerID=8YFLogxK

U2 - 10.1136/jcp-2022-208462

DO - 10.1136/jcp-2022-208462

M3 - Article

C2 - 36198483

SN - 0021-9746

VL - 77

SP - 34

EP - 39

JO - Journal of Clinical Pathology

JF - Journal of Clinical Pathology

IS - 1

ER -

Preferential MGMT hypermethylation in SDH-deficient wild-type GIST

Abstract

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Keywords

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