Genetics of vestibular schwannoma : Genetic landscape of irradiated and radiation-naïve benign and malignant vestibular schwannoma

Abstract

Background: Vestibular schwannoma (VS) is a benign intracranial neoplasm associated with reduced quality of life. Malignant peripheral nerve sheath tumor of the vestibular nerve (VN-MPNST) is the malignant counterpart, an exceedingly rare cancer associated with high mortality. The genetics underlying VS and its etiology is not well understood and the genome of irradiated VS and VN-MPNST has not been characterized. We addressed these shortcomings in this thesis. Material and methods: Tumor specimens from the Bergen neurosurgical tissue bank were subjected to a combination of whole-exome sequencing (WES), whole-genome sequencing and microarray, MLPA, transcriptome sequencing, ViroChip and Sanger sequencing. Results: A median of 14 (4-57) genes were mutated and a median of 0.17% of the autosome was affected by copy number aberrations (CNA) in VS. NF2 mutation was observed in 89%. Tumors with wildtype NF2 harbored mutations in genes linked to NF2. Novel genes and pathways identified in VS included CDC27 (11%), USP8 (7%) and axonal guidance pathway (54%). One clinically aggressive VS was identified and correlated with high mutational burden (231) and mutated RAD54L. Variant allele frequencies for both small mutations and CNAs indicated intratumoral heterogeneity. No plausible virus was associated with VS. We identified a premalignant VS characterized by large chromosomal aberrations and mutated NF2. Malignant transformation was accompanied by whole-genome doubling and mutations in GNAQ, FOXO4 and PDGFRB. VN-MPNST is characterized by gross chromosomal aberrations and homozygous loss of CDKN2A. Previous treatment with GKRS in VS and VN-MPNST did not correlate with neither specific mutations nor genome wide signatures. COSMIC mutational signature 3 contributes to VN-MPNST while signature 6 contributes to a subset of VS.

Conclusion: VS is characterized by intratumoral genetic heterogeneity and relatively few mutations. We found recurrent mutations in NF2 and the axonal guidance pathway in addition to novel genes in subsets. Mutated RAD54L might correlate with a hypermutator phenotype and worse clinical course. We identified CDKN2A as a likely tumor suppressor in both premalignant VS and VN-MPNST. Premalignant VS showed signs of chromosomal instability making it prone to malignant transformation. No biomarker of radioresistance or signature of exposure to ionizing radiation was identified in neither VS nor VN-MPNST. We found no evidence of a viral etiology in VS.