1289. Acquisition of a Hypermutator Phenotype Underlying Distant Spinal Intramedullary Spread in Histone-mutated Diffuse Midline Glioma
Authors: Christopher S. Hong, MD; Christopher Hong, MD; Adam Kundishora, MD; Elena Fomchenko; Zeynep Erson-Omay; Anita Huttner; Asher Marks; Michael Diluna; Kristopher Kahle (New Haven, CT)
Histone-mutated diffuse midline gliomas are high-grade astrocytic tumors with poor prognosis. While these tumors may spread along fiber tracts to local sites and leptomeninges, intramedullary spinal metastases have not been previously reported and the genetic alterations underlying distant spread are poorly understood.
Whole exome sequencing of tumor and germline were performed under standard Yale Center for Genome Analysis practices.
A thirteen-year old male with headaches, nausea, and vomiting was diagnosed with a pineal mass, for which resection demonstrated diffuse midline H3K27M-mutated glioma, followed by proton beam radiation and temozolomide. One year later, he developed lower extremity weakness secondary to bulky intramedullary spinal tumor spread. He underwent cervical and lumbar tumor debulking with pathology confirming distant metastatic spread. Whole exome sequencing was performed for his initial pineal and recurrent spinal specimens. The pineal lesion contained 46 total somatic mutations, including key oncogenic driver mutations in FGFR1, NF1, CACA1D, HOXA9, and H3F3A. The spinal metastatic lesions showed a hypermutated phenotype with increased C>T transition ratio and 10-fold (n=418) increase in somatic mutations, including preservation of 20/46 somatic mutations from the pineal tumor including FGFR1, NF1, HOXA9, and H3F3A as well as further hits in hallmark oncogenes APC, KEL, PTPRB, TRIP11, and MAP3K7. There were additional gained copy number variation/loss of heterozygosity (LOH) events during recurrence including LOH of chr1q, which overlapped with the H3F3A locus resulting in increased variable allele frequency for the mutant allele and subsequent greater abundance of mutated H3F3A. Likewise, there was amplification of chr2p, resulting with associated copy number increase in oncogenes DNMT3A and MYCN.
Though previously unrecognized, histone-mutated midline gliomas are capable of distant intramedullary spinal metastasis. The underlying genetic alterations may be secondary to acquisition of a hypermutation phenotype, resulting in activation of key oncogenes and enhanced mutated H3F3A activity.