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J Natl Cancer Inst. 2014 Dec 7;107(1):384. doi: 10.1093/jnci/dju384. Print 2015 Jan.

Germline mutations in shelterin complex genes are associated with familial glioma.

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Affiliations of authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (MNB, SNJ, HD, LL, JT, DMM, RAG); Codified Genomics, LLC, Houston, TX (MNB); Department of Pediatrics, Division of Hematology-Oncology, Dan L. Duncan Cancer Center (GNA, MMG, AAB, ST, YL, SEP, CCL, DWP, MLB) and Department of Neurosurgery (AJ), Baylor College of Medicine, Houston, TX; Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT (EBC); Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA (EBC); Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH (JBS); Department of Epidemiology and Biostatistics, Georgia State University School of Public Health, Atlanta, GA (DI); Cancer Control and Prevention Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC (DI, JS); Department of Surgery, Duke University Medical Center, Durham, North Carolina (FAO); Cancer and Radiation Epidemiology Unit, Gertner Institute, Chaim Sheba Medical Center, Tel Hashomer (SS); Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel (SiS); Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark (CJ); Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK (RSH); Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN (RBJ, DL); Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY (SHO, JLB); Department of Neurology, NorthShore University HealthSystem, Evanston, IL (RTM); Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA (MRW, KMW); Department of Public Health Services, University of Alberta, Edmonton, Alberta, Canada (FGD); Departments of Neurology, Neurosurgery, and Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA (RL); Department of Biostatistics (Sa


Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

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