The NUP98 Gene as a Potential Modifier of NF2-Associated Tumors

The objective of this exploratory hypothesis-driven award was to investigate whether the NUP98 gene, which plays important roles in nucleocytoplasmic transport, gene expression, mitotic checkpoint, and pathogenesis, is frequently mutated in NF2-related vestibular schwannomas (VS) and whether NUP98 mutations are associated with disease severity. By next-generation sequencing and PCR sequencing, we confirmed that the NUP98 gene was altered more frequently in patient with NF2 than sporadic VS patients or individuals without VS. The alterations in NUP98 identified resulted in changes in three evolutionarily-conserved, charged amino acids, including a D1156N mutation and a Q1142E variant in exon 23 and a K1178R mutation in exon 24. These changes are heterozygous and are present in patients germline. In addition, we found that NF2-associated VS and meningiomas had low mutational burden and did not have mutations in the genes frequently found in sporadic tumors except NF2. Interestingly, multiple VS and meningiomas from the same patient harbored mutations in the same set of genes, and the genomes of these NF2 tumors were quite stable as a recurrent tumor did not have any new mutation over a long period of time despite after several experimental therapies. However, with the number of samples analyzed particularly those from patients with NF2, we were not able to statistically correlate the NUP98 mutations that we identified with disease severity. Additional analysis is ongoing and should allow us to establish whether NUP98 is a potential genetic modifier for NF2.