Lu Xue1,2,3, Weiwei He1,2,3, Yi Zhang4, Zhigang Wang1,2,3, Hongsai Chen1,2,3, Zhe Chen1,2,3, Weidong Zhu1,2,3, Dongmei Liu4, Huan Jia1,2,3, Yi Jiang1,2,3, Zhaoyan Wang1,2,3, Hao Wu1,2,3. 1. Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 3. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China. 4. Euler Technology, Beijing, China.
Abstract
BACKGROUND: Elucidating the mechanism by which biallelic inactivation evolved could provide a mechanistic understanding for NF2 tumorigenesis and also a rationale for clinical management. METHODS: A cohort of 60 NF2 patients was recruited. Next-generation sequencing of tumor and paired control samples was used to explore how NF2 mutations evolve in determining the clinical phenotypes. RESULTS: In total, 60 blood samples (one from each patient) and 61 (from 35 patients) NF2-associated tumors were collected. Next-generation sequencing of the blood samples detected "first hit" NF2 mutation in 35/60 donors (58.3%), 82.9% of which (29/35) bear heterozygous germline mutations, and 17.1% (6/35) of which are mosaics with variable allelic frequency (VAF). While a number of NF2 patients were found without germline mutation, most (57/61, 93.4%) NF2-associated tumors were identified with NF2 somatic mutation. We calculated the correlation between the onset latency of mosaic and germline NF2 allele carriers with the mosaicism VAF. The mosaicism VAF is negatively and linearly correlated to clinical symptom onset latency (R2 = 0.3677, P = .00351), suggesting biallelic inactivation probability is a linear function of "first hit" prevalence in the body. The second NF2 somatic mutation occurrence time positively correlates with the onset of clinical symptoms (R2 = 0.4151, P = .02633), suggesting tumor growth is linearly proportional to the time after biallelic inactivation. CONCLUSIONS: Our results suggested that biallelic inactivation of NF2 evolved through neutral drift and preexisting first hit NF2 allele determines certain aspects of the clinical symptoms. Genetic diagnosis should be included in the diagnostic criteria and treatment consideration of NF2.
BACKGROUND: Elucidating the mechanism by which biallelic inactivation evolved could provide a mechanistic understanding for NF2 tumorigenesis and also a rationale for clinical management. METHODS: A cohort of 60 NF2 patients was recruited. Next-generation sequencing of tumor and paired control samples was used to explore how NF2 mutations evolve in determining the clinical phenotypes. RESULTS: In total, 60 blood samples (one from each patient) and 61 (from 35 patients) NF2-associated tumors were collected. Next-generation sequencing of the blood samples detected "first hit" NF2 mutation in 35/60 donors (58.3%), 82.9% of which (29/35) bear heterozygous germline mutations, and 17.1% (6/35) of which are mosaics with variable allelic frequency (VAF). While a number of NF2 patients were found without germline mutation, most (57/61, 93.4%) NF2-associated tumors were identified with NF2 somatic mutation. We calculated the correlation between the onset latency of mosaic and germline NF2 allele carriers with the mosaicism VAF. The mosaicism VAF is negatively and linearly correlated to clinical symptom onset latency (R2 = 0.3677, P = .00351), suggesting biallelic inactivation probability is a linear function of "first hit" prevalence in the body. The second NF2 somatic mutation occurrence time positively correlates with the onset of clinical symptoms (R2 = 0.4151, P = .02633), suggesting tumor growth is linearly proportional to the time after biallelic inactivation. CONCLUSIONS: Our results suggested that biallelic inactivation of NF2 evolved through neutral drift and preexisting first hit NF2 allele determines certain aspects of the clinical symptoms. Genetic diagnosis should be included in the diagnostic criteria and treatment consideration of NF2.
Authors: K D Hadfield; M J Smith; J E Urquhart; A J Wallace; N L Bowers; A T King; S A Rutherford; D Trump; W G Newman; D G Evans Journal: Oncogene Date: 2010-08-23 Impact factor: 9.867
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Authors: D M Parry; M M MacCollin; M I Kaiser-Kupfer; K Pulaski; H S Nicholson; M Bolesta; R Eldridge; J F Gusella Journal: Am J Hum Genet Date: 1996-09 Impact factor: 11.025
Authors: Moritz Gerstung; Clemency Jolly; Ignaty Leshchiner; Stefan C Dentro; Santiago Gonzalez; Daniel Rosebrock; Thomas J Mitchell; Yulia Rubanova; Pavana Anur; Kaixian Yu; Maxime Tarabichi; Amit Deshwar; Jeff Wintersinger; Kortine Kleinheinz; Ignacio Vázquez-García; Kerstin Haase; Lara Jerman; Subhajit Sengupta; Geoff Macintyre; Salem Malikic; Nilgun Donmez; Dimitri G Livitz; Marek Cmero; Jonas Demeulemeester; Steven Schumacher; Yu Fan; Xiaotong Yao; Juhee Lee; Matthias Schlesner; Paul C Boutros; David D Bowtell; Hongtu Zhu; Gad Getz; Marcin Imielinski; Rameen Beroukhim; S Cenk Sahinalp; Yuan Ji; Martin Peifer; Florian Markowetz; Ville Mustonen; Ke Yuan; Wenyi Wang; Quaid D Morris; Paul T Spellman; David C Wedge; Peter Van Loo Journal: Nature Date: 2020-02-06 Impact factor: 49.962
Authors: Konrad J Karczewski; Laurent C Francioli; Grace Tiao; Beryl B Cummings; Jessica Alföldi; Qingbo Wang; Ryan L Collins; Kristen M Laricchia; Andrea Ganna; Daniel P Birnbaum; Laura D Gauthier; Harrison Brand; Matthew Solomonson; Nicholas A Watts; Daniel Rhodes; Moriel Singer-Berk; Eleina M England; Eleanor G Seaby; Jack A Kosmicki; Raymond K Walters; Katherine Tashman; Yossi Farjoun; Eric Banks; Timothy Poterba; Arcturus Wang; Cotton Seed; Nicola Whiffin; Jessica X Chong; Kaitlin E Samocha; Emma Pierce-Hoffman; Zachary Zappala; Anne H O'Donnell-Luria; Eric Vallabh Minikel; Ben Weisburd; Monkol Lek; James S Ware; Christopher Vittal; Irina M Armean; Louis Bergelson; Kristian Cibulskis; Kristen M Connolly; Miguel Covarrubias; Stacey Donnelly; Steven Ferriera; Stacey Gabriel; Jeff Gentry; Namrata Gupta; Thibault Jeandet; Diane Kaplan; Christopher Llanwarne; Ruchi Munshi; Sam Novod; Nikelle Petrillo; David Roazen; Valentin Ruano-Rubio; Andrea Saltzman; Molly Schleicher; Jose Soto; Kathleen Tibbetts; Charlotte Tolonen; Gordon Wade; Michael E Talkowski; Benjamin M Neale; Mark J Daly; Daniel G MacArthur Journal: Nature Date: 2020-05-27 Impact factor: 69.504