Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21

Abstract Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas prese...

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Published in:	Brain (London, England : 1878) Vol. 146; no. 7; pp. 2861 - 2868
Main Authors:	Sadler, Katherine V, Bowes, John, Rowlands, Charlie F, Perez-Becerril, Cristina, van der Meer, C Mwee, King, Andrew T, Rutherford, Scott A, Pathmanaban, Omar N, Hammerbeck-Ward, Charlotte, Lloyd, Simon K W, Freeman, Simon R, Williams, Ricky, Hannan, Cathal John, Lewis, Daniel, Eyre, Steve, Evans, D Gareth, Smith, Miriam J
Format:	Journal Article
Language:	English
Published:	US Oxford University Press 03-07-2023
Subjects:	Genome-Wide Association Study Humans Neurilemmoma - genetics Neurilemmoma - pathology Neurofibromatoses - genetics Neurofibromatosis 2 - genetics Neuroma, Acoustic - genetics Original Skin Neoplasms - genetics Transcription Factors - genetics GWAS NF2 VS sporadic VS vestibular schwannoma
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Summary:	Abstract Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants. To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10−13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis. Sadler et al. report the results of a genome-wide association study investigating genetic contributors to the risk of sporadic vestibular schwannoma development, and reveal a highly significant risk locus (9p21.3). With 911 cases and 5500 controls, this is the first comprehensive GWAS investigating sporadic vestibular schwannoma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 D Gareth Evans and Miriam J Smith contributed equally to this work.
ISSN:	0006-8950 1460-2156
DOI:	10.1093/brain/awac478