Abstract 3646: (Epi-)genomic homogeneity in radiation-induced glioblastoma with recurrent PDGFRA amplification and loss of CDKN2A/B following primary acute lymphatic leukemia and medulloblastoma
Authors: Deng Maximilian Y. , Sturm Dominik , Pfaff Elke , Balasubramanian Gnana P. , Schittenhelm Jens , Ebinger Martin , Schuhmann Martin U. , Korshunov Andrey , Deimling Andreas von , Witt Olaf , Pfister Stefan M. , Jones David T. 
Published: August 2019

Abstract
As an essential pillar of today’s cancer treatment, radiation therapy 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 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 de novo glioblastoma, and histopathological features to distinguish RIGs from their sporadic counterparts are lacking. Recent large-scale genomic and epigenomic analyses have revealed key genetic alterations in various types of CNS tumors. Here, we performed comprehensive (epi-)genomic and gene expression profiling of RIGs following radiation therapy for primary MB (n=24) and ALL (n=8). DNA methylation profiling demonstrates a high similarity of global DNA methylation patterns among RIGs, regardless of the primary malignancy. Known genetic alterations in high-grade gliomas such as PDGFRA amplification (53%, 17/32) and loss of CDKN2A/B (63%, 20/32) 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 frequently observed in high-grade glioma subtypes of children and young adults. Germline alterations causing cancer predisposition syndromes were not found more frequently in RIG patients than in patients suffering from high-grade gliomas without previous irradiation treatment. The genetic homogeneity of RIGs with the absence of histone 3 and IDH1/2 mutations suggests that RIGs share a common cell of origin, which might be particularly vulnerable to radiation. We performed in vitro drug screens on patient-derived RIG tumor spheres, exhibiting amplified and overexpressed PDGFRA, alongside with non-PDGFRA-amplified GBM cell lines to assess the potential efficacy of RTK inhibitors. The median latency time between cranial irradiation and RIG occurrence was 4.5 years (range: 2.5-15). Patients treated for ALL were diagnosed with RIG at age 9-14 years, exposing a particularly vulnerable but narrow time frame for RIG occurrence in ALL patients, in contrast to RIG patients treated for MB (range: 3-39 years). In summary, our study uncovers diagnostic biomarkers and potential targetable alterations in RIG, which could become relevant for the stratification into future clinical trials with e.g. specific RTK inhibitors, with the objective of improving the outcome of survivors of childhood cancer.
Citation Format: Maximilian Y. Deng, Dominik Sturm, Elke Pfaff, Gnana P. Balasubramanian, Jens Schittenhelm, Martin Ebinger, Martin U. Schuhmann, Andrey Korshunov, Andreas von Deimling, Olaf Witt, Stefan M. Pfister, David T. Jones. (Epi-)genomic homogeneity in radiation-induced glioblastoma with recurrent PDGFRA amplification and loss of CDKN2A/B following primary acute lymphatic leukemia and medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3646.