Dataset Information

Genomics, Epigenetics, and Hearing Loss in Neurofibromatosis Type 2.

ABSTRACT: OBJECTIVES:In this review, we discuss current knowledge about the genetics and epigenetics of vestibular schwannoma (VS) in relation to hearing loss. A multistep and sequential genetic algorithm suitable for the identification of Neurofibromatosis Type 2 (NF2) constitutional and somatic mutations is discussed. DATA SOURCES, STUDY SELECTION:A review was performed of the English literature from 1990 to 2019 using PubMed regarding genetics and epigenetics of vestibular schwannoma and NF2. CONCLUSION:NF2 is a genetic disorder characterized by NF2 mutations that affect the function of a tumor suppressor called merlin. In particular, individuals with NF2 develop bilateral VS that can lead to hearing loss and even deafness. Recent advances in genetic and epigenetic studies have improved our understanding of the genotype-phenotype relationships that affect hearing in NF2 patients. Specific constitutional NF2 mutations including particular truncating, deletion, and missense mutations have been associated with poorer hearing outcomes and more severe clinical manifestations. Epigenetic events, such as DNA methylation and histone modifications, also contribute to the development and progression of hearing loss in NF2 patients. Furthermore, the accumulation of multiple NF2 and non-NF2 genetic and epigenetic abnormalities at the level of the tumor may contribute to worse hearing outcomes. Understanding genetic and epigenetic signatures in individual NF2 patients and particularly in each VS will allow us to develop novel gene therapies and precision medicine algorithms to preserve hearing in NF2 individuals.

SUBMITTER: Dinh CT

PROVIDER: S-EPMC7547625 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Genomics, Epigenetics, and Hearing Loss in Neurofibromatosis Type 2.

Dinh Christine T CT Nisenbaum Eric E Chyou Darius D Misztal Carly C Yan Denise D Mittal Rahul R Young Juan J Tekin Mustafa M Telischi Fred F Fernandez-Valle Cristina C Liu Xue-Zhong XZ

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 20200601 5

<h4>Objectives</h4>In this review, we discuss current knowledge about the genetics and epigenetics of vestibular schwannoma (VS) in relation to hearing loss. A multistep and sequential genetic algorithm suitable for the identification of Neurofibromatosis Type 2 (NF2) constitutional and somatic mutations is discussed.<h4>Data sources, study selection</h4>A review was performed of the English literature from 1990 to 2019 using PubMed regarding genetics and epigenetics of vestibular schwannoma and ...[more]

PMID: 32150022

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Project description:PURPOSE:Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. PATIENTS AND METHODS:Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. RESULTS:Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ? 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell-derived factor 1? (P = .037 and .025, respectively). CONCLUSION:Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.

Dataset Information

Genomics, Epigenetics, and Hearing Loss in Neurofibromatosis Type 2.

Publications

Genomics, Epigenetics, and Hearing Loss in Neurofibromatosis Type 2.

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