Genetic Analysis of Intracranial Schwannomas: Differential NF2 Alteration Frequencies in Nonvestibular Schwannomas Versus Vestibular Schwannomas.

BACKGROUND AND OBJECTIVES

Intracranial schwannomas are benign peripheral nerve sheath tumors usually identified as vestibular schwannomas (VSs). Among nonvestibular intracranial schwannomas (non-VSs), trigeminal and jugular foramen schwannomas are predominantly observed. Although the loss of NF2 function plays a significant role in sporadic VS tumorigenesis, a recent large-scale study showed the involvement of other recurrent gene mutations, in addition to the SH3PXD2A-HTRA1 gene fusion, in sporadic schwannomas. However, the genetic landscape of non-VS remains unclear.

METHODS

We performed targeted panel sequencing and microsatellite analysis of 22q in 51 patients with sporadic intracranial schwannomas, including 30 patients with non-VS and 21 with VS, and explored the differences in the genetic backgrounds between non-VS and VS.

RESULTS

NF2 somatic mutations were frequently identified in tumor samples (25 patients, 49%); non-VS showed a significantly lower frequency of NF2 mutations than VS (26.7% vs 80.9%, respectively; P = 1.8 × 10-4). Despite no differences in the frequency of 22q loss of heterozygosity between non-VS and VS, that of NF2 alterations (NF2 mutation or 22q loss of heterozygosity) was significantly different (56.7% vs 95.2%, respectively, P = 3.2 × 10-3). The NF2, LZTR1, and SMARCB1 germline variants that predispose for NF2 or SMARCB1- and LZTR1-related schwannomatosis were not identified in blood samples; however, low allelic somatic mosaicism was suspected in one case of VS without a typical phenotype. In this article, we demonstrated that in intracranial schwannomas, the frequency of NF2 alterations varied depending on the tumor location, whereas that of other known mutations did not differ between non-VS and VS.

CONCLUSION

Our results suggested the potential involvement of factors other than NF2 inactivation in tumorigenesis, especially in non-VS. However, further comprehensive molecular analyses are warranted.