PT  - JOURNAL ARTICLE
AU  - Chay Paterson
AU  - Ivana Bozic
AU  - Miriam J. Smith
AU  - Xanthe Hoad
AU  - D. Gareth R. Evans
TI  - A mechanistic mathematical model of initiation and malignant transformation in sporadic vestibular schwannoma
AID  - 10.1101/2021.10.03.457528
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.03.457528
4099  - http://biorxiv.org/content/early/2021/10/04/2021.10.03.457528.short
4100  - http://biorxiv.org/content/early/2021/10/04/2021.10.03.457528.full
AB  - A vestibular schwannoma (VS) is a relatively rare, benign tumour of the eighth cranial nerve, often involving alterations to the gene NF2. Previous mathematical models of schwannoma incidence have not attempted to account for alterations in specific genes, and could not distinguish between point mutations and loss of heterozygosity (LOH). Here, we present a mechanistic approach to modelling initiation and malignant transformation in Schwannoma. Each parameter is associated with a specific gene or mechanism operative in Schwann cells, and can be determined by combining incidence data with empirical frequencies of pathogenic variants and LOH. This results in new estimates for the base pair mutation rate u = 4.48 × 10−10 and the rate of LOH = 2.03 × 10−6/yr in Schwann cells. In addition to new parameter estimates, we extend the approach to estimate the risk of both spontaneous and radiation-induced malignant transformation. We conclude that radiotherapy is likely to have a negligible excess risk of malignancy for sporadic VS, with a possible exception of rapidly growing tumours.Competing Interest StatementThe authors have declared no competing interest.