Genomic Characterization of Treatment Induced High Grade Glioma Arising in Survivors of Childhood Cancer Treated with Multi-modality Therapy

Treatment-induced high-grade gliomas (TIHGG) are an incurable late complication of cranial radiation therapy or combined radiation/chemotherapy used to treat pediatric cancer. We assembled a cohort of 35 TIHGG from multiple institutions. The primary antecedent malignancies were medulloblastoma, acute lymphoblastic leukemia, astrocytoma, and ependymoma. Common TIHGG copy number alterations include Chromosome (Ch.). 1p loss/1q gain, Ch. 4 loss, Ch. 6q loss, and Ch. 13 and Ch. 14 loss; focal alterations include PDGFRA and CDK4 gain and loss of CDKN2A and BCOR. Relative to pediatric high-grade glioma (pHGG), BCOR loss (p=0.0004) and CDKN2A loss (p=0.05) were significantly increased. Transcriptomic analysis identified two distinct TIHGG subgroups, one with a low mutation burden (0.12 mut/Mb), Ch. 1p loss/1q gain (5/6 samples), and stem cell characteristics, and one with higher mutation burden (1.08 mut/Mb, p<0.0002), depletion of DNA repair pathways, and inflammatory characteristics. We identified increased chromothripsis in TIHGG versus pHGG (67% vs. 33%, p=0.036), including a sample showing extrachromosomal circular DNA containing PDGFRA and CDK4, a likely amplification mechanism.Â