The genetic landscape of gliomas arising after therapeutic radiation.

Autor: López GY; Department of Pathology, University of California, San Francisco, CA, USA.; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Van Ziffle J; Department of Pathology, University of California, San Francisco, CA, USA.; Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, USA., Onodera C; Department of Pathology, University of California, San Francisco, CA, USA.; Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, USA., Grenert JP; Department of Pathology, University of California, San Francisco, CA, USA.; Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, USA., Yeh I; Department of Pathology, University of California, San Francisco, CA, USA.; Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, USA.; Department of Dermatology, University of California, San Francisco, CA, USA., Bastian BC; Department of Pathology, University of California, San Francisco, CA, USA.; Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, USA.; Department of Dermatology, University of California, San Francisco, CA, USA., Clarke J; Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, CA, USA.; Department of Neurology, University of California, San Francisco, CA, USA., Oberheim Bush NA; Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, CA, USA.; Department of Neurology, University of California, San Francisco, CA, USA., Taylor J; Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, CA, USA.; Department of Neurology, University of California, San Francisco, CA, USA., Chang S; Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, CA, USA., Butowski N; Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, CA, USA., Banerjee A; Division of Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, CA, USA., Mueller S; Department of Neurology, University of California, San Francisco, CA, USA.; Division of Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, CA, USA., Kline C; Department of Neurology, University of California, San Francisco, CA, USA.; Division of Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, CA, USA., Torkildson J; Department of Hematology/Oncology, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA., Samuel D; Department of Hematology/Oncology, Valley Children's Hospital, Madera, CA, USA., Siongco A; Department of Pathology, Valley Children's Hospital, Madera, CA, USA., Raffel C; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Gupta N; Department of Neurological Surgery, University of California, San Francisco, CA, USA.; Department of Pediatrics, University of California, San Francisco, CA, USA., Kunwar S; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Mummaneni P; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Aghi M; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Theodosopoulos P; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Berger M; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Phillips JJ; Department of Pathology, University of California, San Francisco, CA, USA.; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Pekmezci M; Department of Pathology, University of California, San Francisco, CA, USA., Tihan T; Department of Pathology, University of California, San Francisco, CA, USA., Bollen AW; Department of Pathology, University of California, San Francisco, CA, USA., Perry A; Department of Pathology, University of California, San Francisco, CA, USA.; Department of Neurological Surgery, University of California, San Francisco, CA, USA., Solomon DA; Department of Pathology, University of California, San Francisco, CA, USA. david.solomon@ucsf.edu.; Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, USA. david.solomon@ucsf.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2019 Jan; Vol. 137 (1), pp. 139-150. Date of Electronic Publication: 2018 Sep 08.
DOI: 10.1007/s00401-018-1906-z
Abstrakt: 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.
Databáze: MEDLINE
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