Abstract
IntroductionMalignant peripheral nerve sheath tumor of the vestibulocochlear nerve (VN-MPNST) is exceedingly rare and carries a poor prognosis. Little is known about its underlying genetics and in particular the process of malignant transformation. There is an ongoing debate on whether the transformation is initiated by ionizing radiation. We present here the analysis and comparison of two post-radiation VN-MPNST and one undergoing spontaneous transformation.MethodsFour tumors from three patients (radiation-naïve vestibular schwannoma before (VS) and after (VN-MPNST) malignant transformation in addition to two post-radiation VN-MPNST) were subjected to DNA whole-genome microarray and whole-exome sequencing and tumor-specific mutations were called. Mutational signatures were characterized using MuSiCa.ResultsThe tumor genomes were characterized predominantly by copy-number aberrations with 36–81% of the genome affected. Even the VS genome was grossly aberrated. The spontaneous malignant transformation was characterized by a near-total whole-genome doubling, disappearance of NF2 mutation and new mutations in three cancer-related genes (GNAQ, FOXO4 and PDGFRB). All tumors had homozygous loss of the tumor suppressor CDKN2A. Neither mutational signature nor copy number profile was associated with ionizing radiation.ConclusionThe VN-MPNST genome in our cases is characterized by large copy-number aberrations and homozygous deletion of CDKN2A. Our study demonstrates a VS with genetic alterations similar to its malignant counterpart, suggesting the existence of premalignant VS. No consistent mutational signature was associated with ionizing radiation.
Highlights
Malignant peripheral nerve sheath tumor of the vestibulocochlear nerve (VN-Malignant peripheral nerve sheath tumors (MPNST)) is exceedingly rare and carries a poor prognosis
The spontaneous malignant transformation was characterized by a near-total whole-genome doubling, disappearance of NF2 mutation and new mutations in three cancer-related genes (GNAQ, FOXO4 and PDGFRB)
We found no exonic mutations in BRCA1/2, but a copy number aberrations (CNA) affecting either BRCA1 or BRCA2 was evident in all tumors
Summary
Malignant peripheral nerve sheath tumor of the vestibulocochlear nerve (VN-MPNST) is exceedingly rare and carries a poor prognosis. There is an ongoing debate on whether the transformation is initiated by ionizing radiation. Extended author information available on the last page of the article the vestibulocochlear nerve (VN-MPNST) is exceedingly rare and carries a poor prognosis [9]. Gamma Knife Radiosurgery (GKRS) is a type of ionizing radiation (IR) therapy commonly used to treat VS. There are controversies regarding whether IR might induce malignant transformation [27]. Previous studies have found unique mutational signatures attributable to radiation-induced malignancies [3, 32]. IR like gamma rays might cause all types of DNA mutations either directly by ionizing DNA molecules or indirectly by creating free radicals [33]. To assess whether GKRS induces characteristic genomic events, Vol.:(0123456789)
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