Sporadic vestibular schwannoma: a molecular testing summary.

Abstract

Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis. Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in <i>NF2</i> on blood samples for all patients, and tumour DNA samples when available. <i>LZTR1</i> and <i>SMARCB1</i> screening was also performed in patient subgroups. Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline <i>NF2</i> variants were confirmed in 2% of patients. Pathogenic germline variants in <i>LZTR1</i> were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic <i>SMARCB1</i> variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic <i>NF2</i> variants, including those with germline <i>LZTR1</i> pathogenic variants. Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of <i>NF2</i> function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of <i>LZTR1</i>-associated VS tumourigenesis.