DNA Methylation Profiling Separates SDH-Deficient GISTs From KIT-PDGFRA-Driven GISTs and Identifies Predictive Biomarkers for Targeted Therapy
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00669806%3A_____%2F25%3A10499611" target="_blank" >RIV/00669806:_____/25:10499611 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11140/25:10499611
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=VDlhL6zYCz" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=VDlhL6zYCz</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1097/PAS.0000000000002444" target="_blank" >10.1097/PAS.0000000000002444</a>
Alternative languages
Result language
angličtina
Original language name
DNA Methylation Profiling Separates SDH-Deficient GISTs From KIT-PDGFRA-Driven GISTs and Identifies Predictive Biomarkers for Targeted Therapy
Original language description
Succinate dehydrogenase (SDH), a critical enzyme in the citric acid cycle and respiratory electron transport chain, consists of 4 subunits: SDHA, SDHB, SDHC, and SDHD. Deficiency of a single subunit leads to the loss of SDH activity which is implicated in the development of a subset of gastrointestinal stromal tumors (GISTs): SDH-deficient GISTs. These GISTs arise almost exclusively in the stomach, have a female predilection, and primarily affect children and young adults. Their characteristic morphologic features include multinodular architecture, lymphovascular invasion, and lymph node metastasis. At the molecular level, these tumors lack KIT, PDGFRA, BRAF, or NF1 mutations, which are alternative oncogenic drivers typically observed in GIST. Recently, a sarcoma DNA methylation classifier was developed and was shown to be a valuable diagnostic tool. This study evaluated the DNA methylation classifier results for 30 SDH-deficient GISTs and discovered that methylation profiles clustered in a unique region separate from GISTs and leiomyosarcomas. Moreover, MGMT promoter methylation, a predictive biomarker of tumor cell sensitivity to alkylating agent chemotherapy, was identified in 6 primary and 5 metastatic tumors. In addition, 3 primary and 4 metastatic tumors showed gain/low-level amplification of MDM4, which pathologically activates MDM4-p53 axis, a target of inhibitors. In summary, these findings expand the sarcoma DNA methylation classifier to include SDH-deficient GIST as a new sarcoma DNA methylation entity and identified 2 predictive biomarkers for targeted therapy: methylation of MGMT promoter and gain/low-level amplification of MDM4.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30109 - Pathology
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
The American Journal of Surgical Pathology
ISSN
0147-5185
e-ISSN
1532-0979
Volume of the periodical
49
Issue of the periodical within the volume
11
Country of publishing house
US - UNITED STATES
Number of pages
9
Pages from-to
1105-1113
UT code for WoS article
001594204200003
EID of the result in the Scopus database
2-s2.0-105010254260