Abstract
Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras–Raf–MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.
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Acknowledgements
G.Y.L is supported by the National Cancer Institute Training Program in Translational Brain Tumor Research (T32 CA151022). B.C.B. is supported by an NCI Outstanding Investigator Award (R35 CA220481). D.A.S. is supported by the National Institutes of Health Director’s Early Independence Award (DP5 OD021403) and the UCSF Physician-Scientist Scholar Program.
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This study was approved by the Committee on Human Research of the University of California, San Francisco, with a waiver of patient consent.
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López, G.Y., Van Ziffle, J., Onodera, C. et al. The genetic landscape of gliomas arising after therapeutic radiation. Acta Neuropathol 137, 139–150 (2019). https://doi.org/10.1007/s00401-018-1906-z
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DOI: https://doi.org/10.1007/s00401-018-1906-z