Giger, Olivier T;
Ten Hoopen, Rogier;
Shorthouse, David;
Abdullahi, Shukri;
Bulusu, Venkata Ramesh;
Jadhav, Saili;
Maher, Eamonn R;
(2022)
Preferential MGMT hypermethylation in SDH-deficient wild-type GIST.
Journal of Clinical Pathology
10.1136/jcp-2022-208462.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Preferential MGMT hypermethylation in SDH-deficient wild-type GIST |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1136/jcp-2022-208462 |
| Publisher version: | http://dx.doi.org/10.1136/jcp-2022-208462 |
| Language: | English |
| Additional information: | © Author(s) (or their employer[s]) 2022. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Gastrointestinal Neoplasms, Neoplastic Syndromes, Hereditary, Neuroendocrine Tumors, Sarcoma, Stomach Neoplasms |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10158727 |
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