The NUP98 Gene as a Potential Modifier of NF2-Associated Tumors
Abstract
Neurofibromatosis type 2 (NF2) is a devastating genetic disorder characterized by the formation of multiple nervous system tumors, including vestibular schwannomas (VS) and meningiomas. These tumors cause significant morbidities, such as hearing loss, imbalance, facial nerve paralysis, brainstem compression, and, if untreated, death. NF2 patients also exhibit other clinical features, including spinal schwannomas, ependymomas, astrocytomas, and cataracts. Surgery and radiation are the current treatment options; however, complications from treatment are major concerns. While several clinical trials have been initiated, a Food and Drug Administration-approved medical therapy for these tumors is not presently available. A better understanding of the factors contributing to NF2 pathogenesis may aid the identification of new therapeutic targets the design of clinical trials. NF2 patients exhibit a significant degree of variability in clinical features among patients; however, the causes of this heterogeneity are not currently understood. The differences underlying this variation might explain why tumors in certain patients grow faster and why certain patients respond better to a particular treatment. A clearer understanding of the factors responsible for these differences may help stratify patient populations for treatments. Genetic modifiers are changes in the DNA sequence of genes that can affect disease severity, onset, features, and progression. While loss of the neurofibromatosis type 2 gene (NF2) has been shown to play an important role in the development of NF2-associated tumors, it is likely that other modifiers of NF2 pathogenesis exist. We have found that the nucleoporin 98 (NUP98) gene is mutated in NF2 patients with large, fast-growing VS tumors. These mutations are also detected in the blood, indicating that it may be inherited. Further analysis of the NUP98 gene in additional patients showed that these mutations are more frequently found in NF2 patients than in patients with sporadic VS or individuals without a history of VS. In addition, the amino acid residues that are affected by the mutations are preserved in various species throughout evolution, suggesting that changes in these amino acids may be deleterious to NUP98 function. The NUP98 gene encodes proteins involved in protein and RNA transport, cell growth, and gene expression, and mutations in the NUP98 gene have been reported in several types of human cancer. Collectively, this evidence supports the hypothesis that NUP98 may play an important role in NF2 pathogenesis. In this study, we propose to investigate the potential of the NUP98 gene as a genetic modifier of NF2 pathogenesis. We will determine the frequency of NUP98 mutations in NF2-associated and sporadic VS compared to individuals without a history of VS and correlate the presence of NUP98 mutations with clinical parameters, including tumor size, growth rate, number of tumors, age of diagnosis, recurrence, and family history of NF2. The identification of additional genes important in NF2 pathogenesis, such as NUP98, would substantially advance our understanding of the disease and would provide new avenues for NF2 research. Further, if NUP98 mutations are associated with more aggressive clinical features, they may affect disease severity. An immediate clinical impact of this study would be to identify patients who are susceptible to more severe symptoms and may need more attentive treatment. In addition, NUP98 may serve as a novel therapeutic target for the development of therapeutic agents in the future. Ultimately, this study will enhance our understanding of the pathogenesis of and clinical heterogeneity of NF2, which will enable stratification of patient populations and development of novel therapies, leading to better options and outcomes for NF2 patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610104
Entities
People
- Long-Sheng Chang
Organizations
- United States Army