Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B

Abstract

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.

Clinical Characteristics, Treatment Outcomes, And Genetic Alterations of Radiation-Induced Gliomas

“…[6] Recent molecular analysis suggested that RIGs harbor a largely homogeneous genetic and epigenetic pro le of sporadic pediatric receptor tyrosine kinase I GBM, which could be particularly vulnerable to ionizing radiation. [13,14] These clinical and molecular evidences support the use of ReRT in the treatment of RIG. Further studies are needed to con rm the e cacy of ReRT in a large cohort.…”

“…In addition, it also reminded us of the potential risk of developing RIG after radiation therapy for diffuse gliomas and the importance of long-term followup. Prior studies consistently report that RIG does not harbor IDH1/2 mutations [11][12][13], therefore, identifying the wild-type IDH1/2 is diagnostic relevant. We recommend evaluating IDH1/2 mutation status between the primary and secondary gliomas, especially in cases with recurrent glioma occurring long time after successful initial treatment.…”

“…These results are consistent with those of previous reports. [9][10][11][12][13][14] A genetic pro ling study on 12 RIGs found that all tumors lacked alterations in IDH1/2, TERT promoter, H3F3A, chromosome 7 gain, and chromosome 10 loss. In addition, the study reported that radiation-induced high-grade gliomas demonstrated signi cantly increased intrachromosomal copy number breakpoints, likely because of DNA double-strand breaks induced by previous therapeutic radiation.…”

“…[11] Recently, RIG was shown to be characterized by platelet-derived growth factor receptor alpha (PDGFRA) ampli cation, loss of cyclin-dependent kinase inhibitor 2 A and B (CDKN2A/B), and absence of histone 3 or IDH1/2 mutations, suggesting the molecularly distinct gliomagenesis from spontaneous high-grade gliomas. [13] Moreover, drug screening study suggested microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibitors, and proteasome inhibitors as potentially effective therapies. [14] The understanding of the underlying biology will make it possible to provide new therapeutic approaches in the treatment of RIG.…”

“…[6] Moreover, there have been few reports that investigated genetic alterations of RIG. [8][9][10][11][12][13][14] In this study, we investigated the clinical characteristics, treatment outcomes, and genetic alterations of 11 patients with RIG with the aim to identify the optimal follow-up period from the treatment of primary disease, therapeutic strategy, molecular characteristics and their clinical impact of RIG.…”