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Original research
Preferential MGMT hypermethylation in SDH-deficient wild-type GIST
  1. Olivier T Giger1,
  2. Rogier ten Hoopen2,
  3. David Shorthouse3,
  4. Shukri Abdullahi1,
  5. Venkata Ramesh Bulusu4,
  6. Saili Jadhav2,
  7. Eamonn R Maher5,
  8. Ruth T Casey5
  1. 1Pathology, University of Cambridge, Cambridge, UK
  2. 2Oncology, University of Cambridge, Cambridge, UK
  3. 3Department of Medical Physics and Biomedical Engineering, University College London, London, UK
  4. 4Oncology, Addenbrooke's Hospital, Cambridge, UK
  5. 5Department of Medical Genetics and Cancer Research, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr Olivier T Giger, Pathology, University of Cambridge, Cambridge CB2 1TN, UK; olivier.giger{at}nhs.net

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.

  • Gastrointestinal Neoplasms
  • Stomach Neoplasms
  • Sarcoma
  • Neoplastic Syndromes, Hereditary
  • Neuroendocrine Tumors

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.

https://doi.org/10.1136/jcp-2022-208462

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.

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    Footnotes

    • Handling editor Runjan Chetty.

    • Twitter @oligig

    • Contributors OG and RTC: Project design, execution and write up of paper. RTH: write up and analyses. SA: anayses. VRB: clinical data generation. SJ: data analysis. ERM: clinic data generation. OG is responsible for th eoverall content as guarantor.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.