NF1 glioblastoma clonal profiling reveals KMT2B mutations as potential somatic oncogenic events

Although glioblastoma (GBM) is a common malignant brain tumor in older adults in the general population, the incidence of GBM is increased in the neurofibromatosis 1 (NF1) cancer predisposition syndrome, where it tends to arise decades earlier relative to its sporadic counterparts.¹ In contrast to nonsyndromic GBM, NF1-GBM is presumed to arise in the setting of biallelic NF1 inactivation (germline variant and a subsequent somatic mutation).² Because GBM is rare in patients with NF1, the limited number of cases reported has precluded an analysis of tumor ontogeny and evolution. Herein, we leveraged a unique opportunity in which multiple brain samples were obtained at autopsy from a young adult male with a clinical diagnosis of generalized NF1 (established at age 3 years) who died of GBM. When this 27-year-old man initially presented with behavioral changes, neuroimaging revealed a bithalamic tumor (figure 1A), which was pathologically classified as a grade IV astrocytoma (GBM) by stereotactic biopsy. He was treated with cranial radiation and chemotherapy, but exhibited progressive tumor growth and died 39 months after initial diagnosis. At autopsy under an approved IRB protocol, a representative non-neoplastic sample from an unaffected brain region and 5 distinct neoplastic lesions, including thalamus (4 independent samples), anterior commissure (2 independent samples), septum pellucidum (2 independent samples), amygdala (2 independent samples), and cerebellum (1 sample), were obtained.