J Neurol Surg B Skull Base 2014; 75 - A093
DOI: 10.1055/s-0034-1370499

Comparative Genomic Analysis of Grade 1 And Grade 2 Meningiomas in Neurofibromatosis Type 2

Ramita Dewan 1, Alexander Pemov 1, Abhik Ray-Chaudhury 1, Ashok R. Asthagiri 1, Settara C. Chandrasekharappa 1, Douglas R. Stewart 1, Anand V. Germanwala 1
  • 1Bethesda, USA

Introduction: Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder that increases the risk of developing central nervous system tumors, including meningiomas. Although hundreds of constitutional and somatic NF2 mutations have been identified, their influence on tumor aggressiveness and the role of distinct genetic aberrations in meningiomas remain unclear. Recent sequencing studies identified pathogenic AKT1, SMO, TRAF7, and KLF4 variants in sporadic meningiomas, although mutations in these genes were exclusive of mutations in NF2. These studies also noted that sporadic meningiomas with mutant NF2 harbored greater genetic instability and displayed different phenotypes compared with non-NF2 mutant meningiomas. Furthermore, higher-grade meningiomas were reported to have significantly greater numbers of genetic alterations, suggesting the involvement of additional genes in neoplastic tumor transformation. However, these studies were conducted using sporadic meningiomas, and little is known regarding the involvement of genes other than NF2 in NF2-associated meningioma tumorigenesis. We present a case of an NF2 patient who underwent simultaneous resection of two right frontal (anterior and posterior) meningiomas with vastly different growth rates. Final pathology confirmed grade 2 meningioma for the rapidly enlarging and symptomatic anterior tumor and grade 1 meningioma for the relatively radiographically stable posterior tumor. We hypothesized that the differential growth rates of the tumors arose from copy-number differences between the tumors.

Methods: DNA was extracted from both meningioma specimens (including multiple regions within the grade 2 meningioma) and the patient's blood, and was genotyped using the Illumina OmniExpressExome SNP array (∼1 × 106 SNPs) to evaluate intratumoral genetic uniformity and determine whether distinct changes in genetic architecture could be discerned between the two meningiomas.

Results: Both tumors contained an admixture of cells displaying loss of heterozygosity (LOH) at the NF2 locus on chromosome 22 not present in the germline sample. The LOH event in the grade 2 meningioma was a partial deletion of chromosome 22q as compared with a whole chromosome 22 deletion in the grade 1 meningioma. In addition, all samples of the grade 2 meningioma contained additional sites of partial LOH on eight separate chromosomes that were not observed in the germline or posterior tumor samples: six discrete LOH events on chromosome 1, two discrete LOH events on chromosomes 2 and 6, and one LOH event each on chromosomes 11, 12, 14, 18, and the X chromosome. The deletions varied widely in size (∼80 Kb at 14q31.1 to ∼100 Mb on chromosome 6q). In contrast, other than the deletion of one copy of chromosome 22, we did not detect any significant aberrations in the genome of the grade 1 meningioma. Copy-number heterogeneity within the grade 2 meningioma was not observed.

Conclusion: This study utilized high-resolution SNP arrays to genotype a grade 1 and a grade 2 meningioma with differential growth rates from the same NF2 patient. In support of our hypothesis, we observed an increased number of LOH events in the grade 2 (faster growing) meningioma. Many of these loci have not been previously associated in NF2 meningiomas. Whole-exome sequencing of these tumors is planned.