DNA Methylation Profiling Separates SDH-Deficient GISTs From KIT-PDGFRA-Driven GISTs and Identifies Predictive Biomarkers for Targeted Therapy.

Abstract

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 .