Abstract Radiation-induced gliomas (RIGs) are rare, highly aggressive secondary malignancies in pediatric cancer survivors that are biologically distinct from de novo high-grade gliomas. We report a unique case of a 15-year-old pediatric leukemia survivor who developed molecularly distinct, metachronous radiation-associated high-grade gliomas. The patient was treated with bone marrow transplantation and whole-body irradiation (12 cGy) and presented seven years after completion of therapy with a right frontoparietal, infiltrative, non-metastatic high-grade glioma. Methylation profiling classified the tumor as diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype with MGMT promoter methylation. Fusion analysis showed MET exon 14 skipping, and paired exome sequencing demonstrated concurrent MET amplification. He underwent near-total resection followed by focal radiotherapy with concurrent temozolomide, then maintenance lomustine/temozolomide as per ACNS0423, with subsequent temozolomide monotherapy due to prolonged cytopenia. Eleven months from his initial RIG diagnosis, surveillance imaging showed a distant contralateral frontal lobe recurrence. He was treated with gross total resection. Methylation profiling again revealed a pediatric-type high-grade glioma with MGMT promoter methylation. However, this tumor demonstrated absence of the original MET alterations and emergence of novel PDGFRA alterations involving exons 11 and 12 (juxtamembrane domain), and retained similar copy number alterations. Pertinent negatives include no loss of CDKN2A/B with no evidence of a germline cancer predisposition syndrome. Review of the literature shows radiation-induced gliomas frequently harbor molecular alterations distinct from de novo pediatric high-grade gliomas, with most common alteration seen in the receptor tyrosine kinase pathway, including PDGFRA variants. Notably, metachronous radiation-associated high-grade gliomas with mutually exclusive driver alterations such as our case are rarely described. Our case highlights the molecular heterogeneity of RIGs and underscores the importance of repeat molecular profiling raising important questions of tumor evolution at recurrence to guide diagnosis and therapeutic decision-making.
Brandt et al. (Tue,) studied this question.