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Acta Neuropathologica

, Volume 137, Issue 1, pp 139–150 | Cite as

The genetic landscape of gliomas arising after therapeutic radiation

  • Giselle Y. López
  • Jessica Van Ziffle
  • Courtney Onodera
  • James P. Grenert
  • Iwei Yeh
  • Boris C. Bastian
  • Jennifer Clarke
  • Nancy Ann Oberheim Bush
  • Jennie Taylor
  • Susan Chang
  • Nicholas Butowski
  • Anuradha Banerjee
  • Sabine Mueller
  • Cassie Kline
  • Joseph Torkildson
  • David Samuel
  • Aleli Siongco
  • Corey Raffel
  • Nalin Gupta
  • Sandeep Kunwar
  • Praveen Mummaneni
  • Manish Aghi
  • Philip Theodosopoulos
  • Mitchel Berger
  • Joanna J. Phillips
  • Melike Pekmezci
  • Tarik Tihan
  • Andrew W. Bollen
  • Arie Perry
  • David A. SolomonEmail author
Original Article

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.

Keywords

Secondary malignancy Radiation therapy Ionizing radiation Radiation-associated glioma Radiation-induced glioma (RIG) DNA double-strand breaks Chromosome breaks Genomic signature Mutational signature Glioblastoma Astrocytoma Ganglioglioma 

Notes

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.

Compliance with ethical standards

Ethical approval

This study was approved by the Committee on Human Research of the University of California, San Francisco, with a waiver of patient consent.

Conflict of interest

The authors declare that they have no competing interests related to this study.

Supplementary material

401_2018_1906_MOESM1_ESM.xlsx (68 kb)
Supplementary material 1 (XLSX 68 kb)
401_2018_1906_MOESM2_ESM.pdf (11.5 mb)
Supplementary material 2 (PDF 11779 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Giselle Y. López
    • 1
    • 2
  • Jessica Van Ziffle
    • 1
    • 3
  • Courtney Onodera
    • 1
    • 3
  • James P. Grenert
    • 1
    • 3
  • Iwei Yeh
    • 1
    • 3
    • 4
  • Boris C. Bastian
    • 1
    • 3
    • 4
  • Jennifer Clarke
    • 5
    • 6
  • Nancy Ann Oberheim Bush
    • 5
    • 6
  • Jennie Taylor
    • 5
    • 6
  • Susan Chang
    • 5
  • Nicholas Butowski
    • 5
  • Anuradha Banerjee
    • 7
  • Sabine Mueller
    • 6
    • 7
  • Cassie Kline
    • 6
    • 7
  • Joseph Torkildson
    • 8
  • David Samuel
    • 9
  • Aleli Siongco
    • 10
  • Corey Raffel
    • 2
  • Nalin Gupta
    • 2
    • 11
  • Sandeep Kunwar
    • 2
  • Praveen Mummaneni
    • 2
  • Manish Aghi
    • 2
  • Philip Theodosopoulos
    • 2
  • Mitchel Berger
    • 2
  • Joanna J. Phillips
    • 1
    • 2
  • Melike Pekmezci
    • 1
  • Tarik Tihan
    • 1
  • Andrew W. Bollen
    • 1
  • Arie Perry
    • 1
    • 2
  • David A. Solomon
    • 1
    • 3
    Email author
  1. 1.Department of PathologyUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of Neurological SurgeryUniversity of CaliforniaSan FranciscoUSA
  3. 3.Clinical Cancer Genomics LaboratoryUniversity of CaliforniaSan FranciscoUSA
  4. 4.Department of DermatologyUniversity of CaliforniaSan FranciscoUSA
  5. 5.Division of Neuro-Oncology, Department of Neurological SurgeryUniversity of CaliforniaSan FranciscoUSA
  6. 6.Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  7. 7.Division of Hematology/Oncology, Department of PediatricsUniversity of CaliforniaSan FranciscoUSA
  8. 8.Department of Hematology/OncologyUCSF Benioff Children’s Hospital OaklandOaklandUSA
  9. 9.Department of Hematology/OncologyValley Children’s HospitalMaderaUSA
  10. 10.Department of PathologyValley Children’s HospitalMaderaUSA
  11. 11.Department of PediatricsUniversity of CaliforniaSan FranciscoUSA

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