Molecular Characterization of Radiation-induced Glioblastoma

Radiation therapy represents an essential pillar of today's cancer treatment and has led to improved survival rates of patients with childhood malignancies including leukemia and central nervous system (CNS) tumors. However, long-term complications such as radiation-induced malignancies can occur in a subset of patients following radiation therapy, especially observed in pediatric patients due to their long follow-up period in case of survival. Radiation-induced glioblastomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). Histopathologically, most RIGs are best described as high grade gliomas resembling their sporadic counterparts, and histopathologic features to distinguish RIGs from de-novo glioblastoma are lacking.

Recent large-scale genomic and epigenomic analyses have provided insight into key genetic alterations in various types of CNS tumors. In our study, we analyzed RIGs from 21 patients with MB and 8 patients with ALL as primary malignancy. DNA methylation profiling demonstrates a high similarity of global DNA methylation patterns among RIGs. Known genetic alterations in high-grade gliomas such as PDGFRA amplification and loss of CDKN2A/B frequently occur in RIGs. None of the RIGs harbored somatic hotspot mutations in genes encoding histone variants H3.3 and H3.1/H3.2 or IDH1/2, which are usually frequently observed in pediatric high-grade glioma subtypes. Germline mutations causing cancer predisposition syndromes were not found more frequently in RIG patients than in patients suffering from de-novo high-grade gliomas.

The genetic homogeneity of RIGs with the absence of IDH1/2 and histone 3 mutations suggests that RIGs might share a common cell of origin, which could be particularly vulnerable to radiation.