Presenter(s)
W. Y. Suh1, B. H. Kang2, S. Lee3, J. Jung4, and J. H. Lee1,4; 1Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea, Republic of (South), 2Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Korea, Republic of (South), 3Department of Genomic Medicine, Seoul National University Hospital, Seoul, Korea, Republic of (South), 4Cancer Research Institute, Seoul National University, Seoul, Korea, Republic of (South)
Purpose/Objective(s):
Despite standard radiotherapy, outcomes of high-grade gliomas (HGG) remain heterogeneous, underscoring the need for molecular biomarkers that predict radiation response. While common genomic alterations are well-documented, the clinical and biological significance of infrequent events, such as SETD2 loss, remains under-explored. Although SETD2 is widely regarded as a tumor suppressor in other solid tumors, its role in modulating radiosensitivity and clinical outcomes in HGG remains unclear. We therefore investigated the clinical and functional implications of SETD2 alterations in HGG, with a particular focus on radiation response.
Materials/Methods:
We performed an integrative analysis combining institutional and public datasets (MSKCC, TCGA, CGGA, and GLASS). A retrospective cohort of 220 primary HGG patients from Seoul National University Hospital (SNUH) was analyzed. Survival impact was evaluated using multivariable Cox regression analysis adjusting for established clinical and molecular variables. SETD2 expression was compared across molecular subtypes. Functional validation was conducted in U87MG glioblastoma cell lines and patient-derived tumorspheres using shRNA-mediated knockdown and pharmacologic inhibition with EZM0414. Radiation response was assessed through proliferation and radiosensitivity assays.
Results:
Multivariable Cox analysis of integrated SNUH, MSKCC, and TCGA cohorts demonstrated that SETD2 loss-of-function mutation was significantly associated with improved survival in both HGG (HR=0.53, 95% CI: 0.31–0.89, p=0.017) and IDH-wildtype glioblastoma (HR=0.52, 95% CI: 0.29–0.93, p=0.028). Lower SETD2 expression also predicted significantly better survival across independent cohorts, including CGGA (p<0.0001), TCGA IDH-wildtype GBM (p=0.0074), and GLASS IDH-wildtype HGG (p=0.0016). Notably, SETD2 expression was significantly lower in the mitochondrial subtype, a subgroup characterized by relatively favorable prognosis and increased radiosensitivity. In vitro validation further supported a radiation-specific effect. In U87MG cells, SETD2 knockdown significantly inhibited proliferation and enhanced radiosensitivity. Similarly, in patient-derived glioblastoma tumorspheres, SETD2 knockdown markedly increased radiation-induced growth suppression. Pharmacologic inhibition with EZM0414 recapitulated these effects, further potentiating radiation response.
Conclusion:
SETD2 deficiency is associated with improved survival and enhanced radiosensitivity in high-grade gliomas, particularly in IDH-wildtype glioblastoma. Contrary to its traditional tumor suppressor role in other malignancies, SETD2 loss in HGG appears to define a biologically distinct and radiation-responsive subgroup. These findings suggest that SETD2 loss may serve as a predictive biomarker of radiation response and represent a potential therapeutic vulnerability for radiosensitization strategies.