PreferentialMGMThypermethylation in SDH-deficient wild-type GIST
| Autor: | Olivier T Giger, Rogier ten Hoopen, David Shorthouse, Shukri Abdullahi, Venkata Ramesh Bulusu, Saili Jadhav, Eamonn R Maher, Ruth T Casey |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal of Clinical Pathology. :jcp-2022 |
| ISSN: | 1472-4146 0021-9746 |
| DOI: | 10.1136/jcp-2022-208462 |
| Popis: | AimsWild-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 bySDHxinactivation 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.MethodsMGMT 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.ResultsMGMTpromoter 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 (pSDHxsubunit gene mutations or SDHC epimutation status and mean MGMT methylation levels.ConclusionMGMT 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. |
| Databáze: | OpenAIRE |
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