Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

Abstract

Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of all meningiomas, but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas had simple genomes, with fewer mutations, rearrangements and copy-number alterations than reported in other tumors in adults. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements, including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers in an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.

Figure 1

The landscape of somatic alterations in the grade I meningioma genome. (a) Fraction of the genome altered by somatic copy-number alterations (SCNAs), (b) number of somatic intra- and inter-chromosomal rearrangements, and (c) number of non-synonymous mutations in meningiomas and other tumor types. MEN: meningioma; PR: prostate; CRC: colorectal carcinoma; BCL: diffuse large B-cell lymphoma; MEL: melanoma; MM: multiple myeloma; HN: head and neck cancers. (d) Somatic genetic alterations in individual grade I meningiomas of the discovery cohort. Top: Copy-number profiles (red = gain, blue = loss). Middle: Number of somatic rearrangements per tumor. Samples labeled as MENex are exome-sequenced, in which no rearrangements were detected. Bottom: Total non-synonymous and synonymous mutations in exons. ** p<0.01, *** p<0.0001.

Figure 2

Somatic rearrangements disrupt tumor suppressors in several meningiomas. Circos plots show the SCNAs (inner ring heat map) and intra- and inter-chromosomal rearrangements (green and purple arcs, respectively) in three whole-genome sequenced meningiomas. Left: Chromothripsis of chromosome 1 (enlarged in inset) in an NF2-mutated sample (MEN0017) disrupts the putative tumor suppressor NEGR1. Middle: A second NF2-mutated sample (MEN0018) harbors 29 rearrangements including disruption of NEGR1. Right: An inversion on chromosome 22 disrupts NF2, and other rearrangements affect NF1 and CDK14 (MEN0009). Data from the remaining tumors are shown in Supplementary Figure 4.

Figure 3

Significant and selected cancer-related somatic mutations, insertion-deletions, and translocations in meningiomas. Mutation subtypes are denoted by the indicated colors. If multiple mutations were found in a gene in a single sample, only one is shown. Discovery set tumors are in the same order as in Figure 1d. Right: Significance of mutations in each gene, as false discovery rate q-values. The full list of mutated genes is shown in Supplementary Table 4.

Figure 4

Associations between mutations in Hh and Akt/mTOR pathways and histologic findings. (a) AKT/MTOR and SMO-mutated samples are predominantly of the meningothelial subtype (p=0.009, p=0.005). NF2-mutated samples are predominantly fibroblastic and transitional (p=0.013). (b) Immunohistochemistry indicates activation of Hh and Akt/mTOR pathways in tumors harboring SMO and AKT1 mutations, respectively (p=0.0008, p=3×10⁻⁶). GAB1 staining was used as a marker of Hh pathway activation, and STMN1 staining was used as a marker of PI3K/Akt/mTOR pathway activation. Scale bars denote 50 micrometers.