Vestibular schwannomas (VSs) are benign tumors of the eighth cranial nerve and the hallmark of NF2-related schwannomatosis. However, the majority of these tumors occur sporadically, arising from two inactivating alterations of the NF2 gene. In this study, we re-evaluated a total of 29 VSs, each harboring two intragenic pathogenic NF2 variants. In the six NF2-associated VSs, the intra-tumor variant frequencies differed substantially. Three of these cases were mosaic, as the pathogenic NF2 variants were absent in the corresponding blood. By contrast, in the majority (20/23, 87%) of sporadic VSs, the allele frequencies of the two pathogenic NF2 variants were nearly identical. Nevertheless, in two sporadic VSs, the intra-tumor variant frequencies were clearly divergent, suggesting the presence of cells with only one variant—the one with the higher allele frequency. We hypothesize that divergence in intra-tumor variant frequencies may provide a potential genetic indication for mosaic NF2-related schwannomatosis, even in cases that appear sporadic.
Kluwe et al. (Mon,) studied this question.