PROTEOME AND PHOSPHOPROTEOME ANALYSIS IDENTIFIES STAT1 AS A NOVEL TARGET IN DIFFERENT GRADE MENINGIOMAS

Abstract

Meningioma is the most commonly diagnosed primary brain tumor and is associated with significant morbidity. Children treated with therapeutic radiation to the head are at almost ten-fold risk of radiation-associated meningioma (RAM). RAM tumors are associated with aggressive histological features and reduced survival but treatment options remain limited. To discover genes associated with RAM we performed whole-exome sequencing on matched constitutional and tumor materials from 20 patients treated in childhood with ionizing radiation to the head and subsequently diagnosed with cranial meningioma. The mean number of protein-altering somatic mutations was 139.2 (median=94, range=49-541) and did not vary significantly by sex, grade, age at initial or meningioma diagnosis, time since radiation, dose, meningioma location or initial diagnosis (Acute Lymphoblastic Leukemia (ALL) versus other). The average proportion of the genome with copy number variation (CNV) was 6.4 (range 1.2-15.4). Males had twice the CNV rate of females (8.4 vs 4.8, respectively, p=0.05). Although no other variable was significantly associated with difference in CNV rate, of the 5 patients with a CNV value of 10% or more, 4 (80%) had a prior diagnosis of ALL. Eleven genes with significantly more somatic mutations than expected by chance were identified (NF2, VKORC1, GAB1, METTL25, AK3, IL15RA, MIPOL1, MetAP2, AWAT1, ERO1L, ATP6V0D2). The most common were NF2 (n=4 samples) and AK3 (n=4 samples). Two samples had mutations in MetAP2, a gene that encodes the protein methionine aminopeptidase (MetAP2). MetAP2 inhibitors are currently in use for the treatment of a number of cancers suggesting a possible new treatment for some patients with RAM. Our findings suggest a high rate of mutations in RAM; with the exception of NF2 these changes are dissimilar from those reported in non-radiation associated meningioma.