Identification of common genetic variants as modifiers of risk of vestibular schwannoma

Abstract

Vestibular schwannomas (VS) are benign tumours that arise on the vestibular branch of the vestibulocochlear nerve. Accounting for approximately 9% of all non-malignant central nervous system tumours, VS frequently cause hearing loss amongst other symptoms in patients. VS are known to occur in the context of tumour suppressor syndromes, neurofibromatosis type 2 (NF2) and LZTR1-associated schwannomatosis. However, most VS present sporadically in patients without further features of NF2 or schwannomatosis. Currently, no germline variants are associated with predisposition to sporadic VS in the absence of NF2 and schwannomatosis disease. This study aims to further the understanding of the genetic landscape that surrounds VS predisposition through different branches of research into the biological features of VS. Characterisation of genotypic features for both germline and somatic samples in sporadic and syndromic forms of VS was conducted through a review of molecular testing in VS patients. Biallelic inactivation of NF2 is frequently observed in somatic sporadic VS samples, suggesting that loss of NF2 function is a common pathway in the development of all VS tumours. Interpretation of missense variants in NF2 remains challenging. Through collation of known NF2 missense variants and corresponding evidence for their clinical interpretation, I highlight the need for incorporation of disease-specific features into variant interpretation guidelines to improve clinical actionability. In a genome-wide association study performed in 911 cases and 5,500 controls I identify a novel risk locus on chromosome 9p21.3 in association with sporadic VS risk. Pathway analysis of the genes encompassed by this region highlights a potential mechanism for susceptibility to VS development when somatic loss of NF2 occurs. Through disease modelling of a known VS susceptibility variant in NF2, I also demonstrate that splice-modulating therapies hold promise in the treatment of NF2 disease caused by deep intronic variants. This study provides new insights and further characterisation of the genomic features that predispose to, and result in, VS tumourigenesis. These findings point towards promising new areas of research into VS predisposition, unified by dysregulation of the oncogenic signalling pathways that involve function of the NF2 protein.

Date of Award	28 Mar 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Dafydd Evans (Co Supervisor) & Miriam Smith (Main Supervisor)