Origins of biallelic inactivation of NF2 in neurofibromatosis type 2.

Lu Xue, Weiwei He, Yi Zhang, Zhigang Wang, Hongsai Chen, Zhe Chen, Weidong Zhu, Dongmei Liu, Huan Jia, Yi Jiang, Zhaoyan Wang, Hao Wu

Neuro-oncology 2022 Jun 01

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Elucidating the mechanism by which biallelic inactivation evolved could provide a mechanistic understanding for NF2 tumorigenesis and also a rationale for clinical management. A cohort of 60 NF2 patients was recruited. Next-generation sequencing of tumor and paired control samples was used to explore how NF2 mutations evolve in determining the clinical phenotypes. In total, 60 blood samples (one from each patient) and 61 (from 35 patients) NF2-associated tumors were collected. Next-generation sequencing of the blood samples detected "first hit" NF2 mutation in 35/60 donors (58.3%), 82.9% of which (29/35) bear heterozygous germline mutations, and 17.1% (6/35) of which are mosaics with variable allelic frequency (VAF). While a number of NF2 patients were found without germline mutation, most (57/61, 93.4%) NF2-associated tumors were identified with NF2 somatic mutation. We calculated the correlation between the onset latency of mosaic and germline NF2 allele carriers with the mosaicism VAF. The mosaicism VAF is negatively and linearly correlated to clinical symptom onset latency (R2 = 0.3677, P = .00351), suggesting biallelic inactivation probability is a linear function of "first hit" prevalence in the body. The second NF2 somatic mutation occurrence time positively correlates with the onset of clinical symptoms (R2 = 0.4151, P = .02633), suggesting tumor growth is linearly proportional to the time after biallelic inactivation. Our results suggested that biallelic inactivation of NF2 evolved through neutral drift and preexisting first hit NF2 allele determines certain aspects of the clinical symptoms. Genetic diagnosis should be included in the diagnostic criteria and treatment consideration of NF2. © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Lu Xue, Weiwei He, Yi Zhang, Zhigang Wang, Hongsai Chen, Zhe Chen, Weidong Zhu, Dongmei Liu, Huan Jia, Yi Jiang, Zhaoyan Wang, Hao Wu. Origins of biallelic inactivation of NF2 in neurofibromatosis type 2. Neuro-oncology. 2022 Jun 01;24(6):903-913