RESUMO
Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. We performed DNA methylation profiling, RNA-seq, and DNA sequencing on 32 RIG tumors and an in vitro drug screen in two RIG cell lines. We report that based on DNA methylation, RIGs cluster primarily with the pediatric receptor tyrosine kinase I high-grade glioma subtype. Common copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, and Ch. 13q and Ch. 14q loss; focal alterations include PDGFRA and CDK4 gain and CDKN2A and BCOR loss. Transcriptomically, RIGs comprise a stem-like subgroup with lesser mutation burden and Ch. 1p loss and a pro-inflammatory subgroup with greater mutation burden and depleted DNA repair gene expression. Chromothripsis in several RIG samples is associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. Drug screening suggests microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors, as potentially effective therapies.
Assuntos
Glioma/genética , Glioma/patologia , Radiação , Adolescente , Criança , Estudos de Coortes , Simulação por Computador , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Gradação de Tumores , Transcriptoma/genética , Adulto JovemRESUMO
Paragangliomas are rare neuroendocrine neoplasms derived from sympathetic or parasympathetic paraganglia and have the ability to secrete catecholamines. We present the case of a 37-year-old asymptomatic female who underwent right ovarian cystectomy for a mature cystic teratoma and was found to have an intra-tumoral paraganglioma. More research is needed to determine metastatic potential as well as the likelihood of recurrence of these unique neoplasms.