Stryker Central Nervous System Tumor Award: Deep Phenotyping identifies Truncating Mutations in the NF2 Alpha-Helical Domain Associated with Disease Severity in Neurofibromatosis Type II

Saturday, May 4, 2024

4:46 PM – 4:50 PM CT

Location: N427bc

Presenting Author(s)

David T. Asuzu, MD, PhD, MPH

Neurosurgery Resident
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke
Bethesda, MD, US

Co-Author(s)

Emma C. Celano, MD

Neurosurgery Resident
Department of Neurological Surgery, MedStar Georgetown University Hospital
Washington, District of Columbia, United States
PC

Prashant Chittiboina, MD, MPH

Investigator
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH.Neurosurgery Unit for Pituitary and Inheritable Disease, NINDS.
Bethesda, Maryland, United States
AE

Abdel Elkahloun, PhD

Staff Scientist
NHGRI, NIH, Bethesda, MD, United States
KJ

Kory Johnson, PhD

Staff Scientist
DIR Bioinformatics Section, National Institute of Neurological Disorders and Stroke, United States
DM

Debjani Mandal, PhD

Staff Scientist
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, United States
DM

Dustin Mullaney, n/a

Post-baccalaureate Fellow
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, United States

Disclosure(s):

David T. Asuzu, MD, PhD, MPH: No financial relationships to disclose

Introduction: Neurofibromatosis type 2 (NF2) is an autosomal dominant tumor syndrome with protean presentation and variable penetrance. Our objective was to perform deep phenotypic and genetic analysis of a diverse NF2 population to identify predictors of worse clinical outcome.

Methods: We evaluated 167 patients with a diagnosis of NF2 and followed them for a mean duration of 4.5 years. Detailed clinical and radiographic characteristics were collected on each patient, and Karnofsky performance scale (KPS) scores and within-study mortality were monitored. CLIA certified genotyping was supplemented with a custom sequencing panel targeting NF2 and other schwannomatosis-related genes. Outcome predictors were assessed using multivariable linear or logistic regression.

Results: Germline mutations (nonsense 36%, splice-site 16%, and large deletions 16%) were grouped by predicted protein effect (truncating 41%, non-truncating 27%, and mosaic 33%) and mapped to the NF2 chromosomal locus. Patients with truncating NF2 mutations had lower mean age of diagnosis (19.9 versus 25.7, P = 0.01) and faster tumor growth rates (2.4% versus 1.1% for all tumors, P = 0.01). Patients whose truncating mutations occurred within the NF2 alpha-helical domain (exons 8, 11 and 12) had more total tumors (adjusted coefficient 15.0, 95% CI 0.8 – 29.0, P = 0.04), and specifically more schwannomas (adjusted coefficient 7.0, 95% CI 0.2 – 13.9, P = 0.04). Presence of alpha-helical domain mutations predicted higher within-study mortality (adjusted OR 4.3, 95% CI 1.1 – 16.2, P = 0.03).

Conclusion : We deeply phenotyped a diverse cohort of NF2 patients and found that the location of truncating mutation predicted disease severity. The NF2 alpha-helical domain functions a hinge, facilitating binding between the tail domain and the LATS binding site within the FERM domain. In our study, truncating mutations in the alpha-helical domain of NF2 were associated with higher tumor burden and over four-fold within-study mortality. The alpha-helical domain may constitute a novel therapeutic target in patients with NF2.