Chay Paterson1, Ivana Bozic2, Miriam J Smith3,4, Xanthe Hoad5, D Gareth R Evans3,4. 1. Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK. chay.paterson@manchester.ac.uk. 2. Department of Applied Mathematics, University of Washington, Seattle, WA, USA. 3. Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK. 4. Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK. 5. Radiation Protection Group, Medical Physics, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Abstract
BACKGROUND: 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 nonsense mutations and loss of heterozygosity (LOH). METHODS: 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. RESULTS: 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. DISCUSSION: 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.
BACKGROUND: 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 nonsense mutations and loss of heterozygosity (LOH). METHODS: 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. RESULTS: 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. DISCUSSION: 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.
Authors: Andreas K Demetriades; Nicholas Saunders; Peter Rose; Cyril Fisher; Jeremy Rowe; Robert Tranter; Carl Hardwidge Journal: Skull Base Date: 2010-09
Authors: Katherine V Sadler; Naomi L Bowers; Claire Hartley; Philip T Smith; Simon Tobi; Andrew J Wallace; Andrew King; Simon K W Lloyd; Scott Rutherford; Omar N Pathmanaban; Charlotte Hammerbeck-Ward; Simon Freeman; Emma Stapleton; Amy Taylor; Adam Shaw; Dorothy Halliday; Miriam Jane Smith; D Gareth Evans Journal: J Med Genet Date: 2020-06-23 Impact factor: 6.318
Authors: K D Hadfield; W G Newman; N L Bowers; A Wallace; C Bolger; A Colley; E McCann; D Trump; T Prescott; D G R Evans Journal: J Med Genet Date: 2008-02-19 Impact factor: 6.318
Authors: Michael E Sughrue; Andrea H Yeung; Martin J Rutkowski; Steven W Cheung; Andrew T Parsa Journal: J Neurosurg Date: 2009-11-27 Impact factor: 5.115
Authors: Roland Goldbrunner; Michael Weller; Jean Regis; Morten Lund-Johansen; Pantelis Stavrinou; David Reuss; D Gareth Evans; Florence Lefranc; Kita Sallabanda; Andrea Falini; Patrick Axon; Olivier Sterkers; Laura Fariselli; Wolfgang Wick; Joerg-Christian Tonn Journal: Neuro Oncol Date: 2020-01-11 Impact factor: 12.300
Authors: Matthew L Carlson; James B Smadbeck; Michael J Link; Eric W Klee; George Vasmatzis; Lisa A Schimmenti Journal: Otol Neurotol Date: 2018-10 Impact factor: 2.311