Adam Hexter1, Adrian Jones2, Harry Joe2, Laura Heap1, Miriam J Smith3, Andrew J Wallace1, Dorothy Halliday4, Allyson Parry5, Amy Taylor6, Lucy Raymond6, Adam Shaw7, Shazia Afridi8, Rupert Obholzer9, Patrick Axon10, Andrew T King11, Jan M Friedman12, D Gareth R Evans13. 1. Manchester Centre for Genomic Medicine, Central Manchester NHS Foundation Trust, St Mary's Hospital, Manchester, UK. 2. Department of Statistics, University of British Columbia, Vancouver, Canada. 3. Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. 4. Medical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 5. Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 6. Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 7. Department of Medical Genetics, Guy's and St. Thomas' Hospital, London, UK. 8. Department of Neurology, Guy's and St. Thomas' Hospital, London, UK. 9. Department of Ear, Nose and Throat, Guy's and St. Thomas' Hospital, London, UK. 10. Department of Otolaryngology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 11. Department of Neurosurgery, Salford Royal NHS Foundation Trust, St. Mary's Hospital, Manchester, UK. 12. Department of Medical Genetics, University of British Columbia, Vancouver, Canada Child & Family Research Institute, Vancouver, Canada. 13. Manchester Centre for Genomic Medicine, Central Manchester NHS Foundation Trust, St Mary's Hospital, Manchester, UK Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Abstract
BACKGROUND: Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype-phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown. METHODS: We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan-Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2. RESULTS: The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6-15 had lower mortality than patients with splice-site mutations in exons 1-5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier. CONCLUSIONS: Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND: Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype-phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown. METHODS: We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan-Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2. RESULTS: The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6-15 had lower mortality than patients with splice-site mutations in exons 1-5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier. CONCLUSIONS: Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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