Gamma Knife Radiosurgery does not alter the copy number aberration profile in sporadic vestibular schwannoma

Abstract

Introduction: Ionizing radiation is a known etiologic factor in tumorigenesis and its role in inducing malignancy in the treatment of vestibular schwannoma has been debated. The purpose of this study was to identify a copy number aberration (CNA) profile or specific CNAs associated with radiation exposure which could either implicate an increased risk of malignancy or elucidate a mechanism of treatment resistance.

Methods: 55 sporadic VS, including 18 treated with Gamma Knife Radiosurgery (GKRS), were subjected to DNA whole-genome microarray and/or whole-exome sequencing. CNAs were called and statistical tests were performed to identify any association with radiation exposure. Hierarchical clustering was used to identify CNA profiles associated with radiation exposure.

Results: A median of 7 (0-58) CNAs were identified across the 55 VS. Chromosome 22 aberration was the only recurrent event. A median aberrant cell fraction of 0.59 (0.25-0.94) was observed, indicating several genetic clones in VS. No CNA or CNA profile was associated with GKRS.

Conclusion: GKRS is not associated with an increase in CNAs or alteration of the CNA profile in VS, lending support to its low risk. This also implies that there is no major issue with GKRS treatment failure being due to CNAs. In agreement with previous studies, chromosome 22 aberration is the only recurrent CNA. VS consist of several genetic clones, addressing the need for further studies on the composition of cells in this tumor.

Keywords: Gamma Knife Radiosurgery; Genetics; Intratumor genetic heterogeneity; Neurosurgery; Vestibular schwannoma; Whole genome microarray.

Fig. 1

Karyogram for sample VS10. Circos plot of copy number and single nucleotide polymorphism probe data for sample VS10, created using the Circos software [37]. The tracks from outside inwards: chromosome numbers, chromosomal position in Mb, copy number and allele patterns. Copy number gains and losses are highlighted in blue and red, respectively. Most chromosomes show a continuous disomic copy number profile with a normal three band allele pattern (allele configurations AA, AB and BB). On chromosome 22, highlighted in the middle, we see an allelic loss (allele configuration A0 and B0) in the region of NF2 followed by a CNN-ROH (allele configuration AA and BB). However, the aberrations are only present in 63% of the cells giving rise to the split in the middle line of the allele pattern

Fig. 2

Vestibular schwannoma consist of more than one major genetic clone. Circos plot of copy number and single nucleotide polymorphism probes in chromosome 22 for four vestibular schwannomas with increasing aberrant cell fraction. The tracks from outside inwards: chromosomal position in Mb on chromosome 22, copy number and allele patterns respectively for four vestibular schwannomas with increasing aberrant cell fraction. All samples demonstrate hemizygous loss of chromosome 22. The outermost sample shows a minor drop in copy number and a barely visible split in the middle line in the allele pattern because only 26% of the cells are aberrated. Moving inwards, the copy number drops and the split in the allele pattern increases, demonstrating an increase in aberrant cell fraction

Fig. 3

GKRS treatment does not affect the genomic CNA profile of vestibular schwannoma. Dendrogram of hierarchical clustering of the autosomal CNA patterns of vestibular schwannomas. Irradiated and radiation-naïve tumors depicted as red and black terminal vertical lines respectively. The clusters are not associated with previous radiation exposure