Sporadic vestibular schwannoma: a molecular testing summary.

OBJECTIVES

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.

METHODS

Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in on blood samples for all patients, and tumour DNA samples when available. and screening was also performed in patient subgroups.

RESULTS

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 variants were confirmed in 2% of patients. Pathogenic germline variants in were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic variants, including those with germline pathogenic variants.

CONCLUSIONS

Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of 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 -associated VS tumourigenesis.