Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas

Abstract

Cranial radiotherapy improves survival of the most common childhood cancers, including brain tumors and leukemia. Unfortunately, long-term survivors are faced with consequences of secondary neoplasia, including radiation-induced meningiomas (RIMs). We characterized 31 RIMs with exome/NF2 intronic sequencing, RNA sequencing and methylation profiling, and found NF2 gene rearrangements in 12/31 of RIMs, an observation previously unreported in sporadic meningioma (SM). Additionally, known recurrent mutations characteristic of SM, including AKT1, KLF4, TRAF7 and SMO, were not observed in RIMs. Combined losses of chromosomes 1p and 22q were common in RIMs (16/18 cases) and overall, chromosomal aberrations were more complex than that observed in SM. Patterns of DNA methylation profiling supported similar cell of origin between RIMs and SMs. The findings indicate that the mutational landscape of RIMs is distinct from SMs, and have significant therapeutic implications for survivors of childhood cranial radiation and the elucidation of the molecular pathogenesis of meningiomas.

Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum Meningiomas

“…Finally, while novel fusions were recently discovered in a subset of meningiomas, 26,27,33 we did not detect any clinically actionable gene fusions in the meningiomas in our study. This may be explained by the fact that the majority of the cases in our cohort have a low-grade histology, whereas gene fusions, such as those involving TERT (telomerase reverse transcriptase), have been described in high-grade meningiomas.…”

“…Fusion oncogenes have been described in several human cancers including meningiomas 26,27 and have been successfully targeted in several tumor types. 28 To assess whether clinically targetable gene fusions were present in posterior fossa meningiomas, we performed targeted RNA fusion gene analysis in all samples using Archer FusionPlex and did not detect any relevant RNA fusion transcripts (►Table 1).…”

The genetic landscape of gliomas arising after therapeutic radiation

“…Two recent studies of radiation- induced meningiomas found that they lacked somatic single nucleotide variants in the most common genes associated with spontaneous meningioma development including NF2 , TRAF7 , AKT1 , SMO , and KLF4 . Instead, they harbored frequent structural rearrangements involving the NF2 tumor suppressor gene, which are only rarely seen in spontaneous meningiomas [1, 28]. Together, these studies provide preliminary evidence that the DNA double-strand breaks caused by ionizing radiation may lead to a distinct genomic signature and gene alterations that drive radiation-induced secondary malignancies.…”

Diagnosis and Treatment of Parasellar Lesions

“…Meningiomas are more prevalent in female patients, and their incidence increases with the age; malignant tumors are, however, more common in men and children [35,36]. They can also occur secondary to radiotherapy performed for other malignancies [37,38]. Diagnosis is made mainly based on both neurological and radiological evaluation, although the pituitary function can be affected as well.…”