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Genetic Alterations in Patients with NF2-Related Schwannomatosis and Sporadic Vestibular Schwannomas
by
, , ,
Jules P. J. Douwes
1,*
,
Ronald van Eijk
2,
Sybren L. N. Maas
2,3,
Jeroen C. Jansen
1
,
Emmelien Aten
4 and
Erik F. Hensen
1 1
Department of Otorhinolaryngology—Head and Neck Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
2
Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
3
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands
4
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(3), 393; https://doi.org/10.3390/cancers17030393
Submission received: 3 December 2024
/
Revised: 11 January 2025
/
Accepted: 22 January 2025
/
Published: 24 January 2025
(This article belongs to the Special Issue Neurofibromatosis)
Simple Summary
Vestibular schwannomas are tumors that occur on the nerve responsible for hearing and balance, the vestibulocochlear nerve. These benign tumors may appear on one side (unilateral) or both sides (bilateral), with bilateral cases often linked to a condition called NF2-related schwannomatosis. This study explored the genetic causes of vestibular schwannomas in three groups: patients with NF2, younger patients with a unilateral tumor, and older patients with a unilateral tumor. By analyzing DNA from the tumors and blood, we aimed to understand the genetic mutations that drive tumor development and how the genetics differed between the three groups. In all patients, it was found that one gene, NF2, played a major role in the development of vestibular schwannomas. However, there were also differences found in the types of genetic mutations and mechanisms involved, offering new insights into how these tumors form and progress.
Abstract
Background: Unilateral (uVS) and bilateral vestibular schwannoma (bVS) are distinct disease types, yet share tumorigenic features. This study examined causative genetic alterations in three groups: patients with NF2-related schwannomatosis (NF2), young patients with uVS (≤30 years), and older patients with uVS (≥40 years). Methods: Lymphocyte and vestibular schwannoma DNA was genetically analyzed. Outcomes included gene involvement, pathogenicity classification, variant type, effect, and location, and loss of heterozygosity (LOH) of chromosome 22. Results: Among 93 patients, 17% had NF2, 39% were ≤30 years with uVS, and 44% were ≥40 years with uVS. In all patients with NF2 (100%), two or more hits were detected in the tumor DNA, whereas patients with uVS had a slightly lower detection rate (89–98%). NF2-related tumors had a higher frequency of nucleotide variants (76%), while LOH events were more common in uVS (64–69%). Variants were mostly identified in NF2, with nonsense variants over-represented in patients with NF2 (38%) and frameshift variants more prevalent in uVS (44–51%). Conclusions: Biallelic NF2 inactivation primarily drives vestibular schwannoma tumorigenesis. In patients with NF2, two pathogenic NF2 variants or one NF2 variant with LOH are common, whereas patients with uVS often exhibit one NF2 variant with LOH. Additionally, variant types differ between patient groups.
