Mutational signature of extracranial meningioma metastases and their respective primary tumors.

Extracranial metastases of intracranial meningiomas are rare. Little is known about the mutational pattern of these tumors and their metastatic seeding. Here, we retrospectively explored the molecular alterations of these metastatic lesions and their respective intracranial tumor manifestations.Histology and genome sequencing were performed in intracranial meningiomas and their extracranial metastatic lesions operated upon between 2002 and 2021. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations.We analyzed the tumors of five patients with clinically suspected metastases of a meningioma using methylome analysis and next generation panel sequencing of the primary tumors as well as the metastatic lesions. Metastases were found in the spinal cord and one in the lung. In four of these patients, molecular analyses confirmed metastatic disease, while the fifth patient was found to harbor two molecularly distinct meningiomas. On pathological assessment, the primary lesions ranged from CNS WHO grades 1 to 3 (integrated molecular-morphologic meningioma classification scores 2 to 6). Of the four true metastatic cases, three out of the four metastasizing tumors harbored alterations in the BAP1 gene, comprising a stop-mutation combined with copy-number loss (WHO grade 1), copy number loss (WHO grade 3) and a frameshift mutation (WHO grade 2). Furthermore, the latter was confirmed to harbor a BAP1 tumor predisposition syndrome. The fourth metastasizing tumor had copy-number losses in NF2 and PTEN. Only one of four showed CDKN2A homozygous deletion; none showed TERT promotor mutation.Our results molecularly confirm true metastatic disease in four meningioma patients. BAP1 gene alterations were the most frequent. Larger cohorts, most likely from multicenter studies are necessary to evaluate the role of BAP-1 alterations to further understand the metastatic spread in meningiomas. for metastatic spread and might indicate patients at risk for metastatic spread. Further explorations within larger cohorts are necessary to validate these findings which might influence the clinical management in the future.

Bevacizumab can induce reactivity to VEGF-C and -D in human brain and tumour derived endothelial cells.

Though clinical trials demonstrated effectiveness of the anti-VEGF antibody bevacizumab (Avastin) in adjuvant therapies for some solid tumours, there are rather few experimental data about cellular effects of bevacizumab on tumour cells and tumour associated endothelial cells. Recent reports demonstrate resistance mechanisms and secondary re-angiogenesis after a transient normalization of tumour vessels. Therefore we investigated the influence of bevacizumab on human glioma cells and human brain derived as well as tumour derived endothelial cells focussing on the role of VEGF-C and -D as potential alternative pro-angiogenic factors. Bevacizumab treatment showed no influence on proliferation after short term exposure (1-5 days) but slowed down endothelial cell proliferation by 25-30% after 14 days treatment. There was no significant induction of apoptosis after short or long term exposure. Tube formation capabilities were significantly impaired by bevacizumab with a continuing effect after 14 days of treatment even after omitting the antibody. VEGF-C and -D had no effect on endothelial cells in untreated or short term treatment groups. However, cells developed responsiveness to these factors in terms of increased proliferation and tube formation after 14 days bevacizumab treatment. Furthermore, bevacizumab induced expression of VEGF-C and -D in glioma cells. Treatment with bevacizumab may induce alterations in human brain and tumour endothelial cells leading to escape mechanisms from anti-VEGF therapy. VEGF-C and -D thus might act as alternative pro-angiogenic factors during anti-VEGF therapy.