Germline Mutations in Shelterin Complex Genes Are Associated With Familial Glioma

JNCI J Natl Cancer Inst (2015) 107(1): dju384 doi:10.1093/jnci/dju384 First published online December 7, 2014 Brief Communication brief communication Germline Mutations in Shelterin Complex Genes Are Associated With Familial Glioma 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 (SaS) and Department of Pathology (KA), University of Texas MD Anderson Cancer Center, Houston, TX; Department of Community and Family Medicine, Department of Genetics, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH (CIA); Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, AZ (PAT); Department of Radiation Sciences Oncology, Umeå University, Umeå, Sweden (BSM). brief communication Correspondence to: Melissa L. Bondy, PhD, Baylor College of Medicine, Mail Stop BCM: 305, Houston, TX 77030-3498 (e-mail: ). Abstract 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. Received: April 10, 2014; Revised: July 2, 2014; Accepted: October 21, 2014 © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: . 1 of 4 Matthew N. Bainbridge, Georgina N. Armstrong, M. Monica Gramatges, Alison A. Bertuch, Shalini N. Jhangiani, Harsha Doddapaneni, Lora Lewis, Joseph Tombrello, Spyros Tsavachidis, Yanhong Liu, Ali Jalali, Sharon E. Plon, Ching C. Lau, Donald W. Parsons, Elizabeth B. Claus, Jill Barnholtz-Sloan, Dora Il’yasova, Joellen Schildkraut, Francis Ali-Osman, Siegal Sadetzki, Christoffer Johansen, Richard S. Houlston, Robert B. Jenkins, Daniel Lachance, Sara H. Olson, Jonine L. Bernstein, Ryan T. Merrell, Margaret R. Wrensch, Kyle M. Walsh, Faith G. Davis, Rose Lai, Sanjay Shete, Kenneth Aldape, Christopher I. Amos, Patricia A. Thompson, Donna M. Muzny, Richard A. Gibbs, Beatrice S. Melin, Melissa L. Bondy; The Gliogene Consortium M. N. Bainbridge et al. | 2 of 4 brief communication families, as previously described (8). Only variants shared among affected individuals within a family were brought forward. We mapped reads and called and annotated variants using previously described methods and prioritized variants that were rare, predicted to disrupt gene function, and occur in genes with reported cancer association or predisposition (Supplementary Methods, available online) (9). With this approach, we identified two previously undescribed protein-changing variants in POT1 (NM_015450:p.G95C, HG19:chr7:g.124503667C>A; NM_015450:p.E450X, HG19:chr7:g. 124481048C>A) in families A and B, respectively (Figure 1; Supplementary Table 2, available online). Subsequently, polymerase chain reaction (PCR) amplification followed by high-throughput sequencing to interrogate POT1 in a cohort of 264 glioma patients from 246 families resulted in the identification of a third, novel protein-changing mutation (NM_015450:p.D617Efs*8, HG19:chr7:g.124464068TTA>T) in family C (Figure 1). Using Sanger sequencing, we verified and determined the genotypes of all available family members in each pedigree (Figure 1). In family A, six members and one obligate carrier were found to harbor the mutation, whereas three of those individuals developed glioma. Similarly, in family B, six individuals Genetic factors in glioma etiology are poorly understood; less than 5% of glioma cases are familial in origin (1), with only a few described by rare genetic syndromes (2). Both long and short telomeres are associated with cancer risk (3). With regards to sporadic glioma, case-control studies examining telomere length have shown inconsistent associations with risk (4,5), possibly confounded by age-dependent interactions with the variant (6). Here, we describe three familial glioma kindreds characterized by mutations in protection of telomeres protein 1 (POT1), whose product is a member of a protein complex that binds to the TTAGGG repeats of telomeres to regulate length and to protect chromosome ends from abnormal events. The Gliogene Consortium recruited 435 glioma families from 14 centers in the United States, Sweden, Denmark, the United Kingdom, and Israel between 2007 and 2011 (7). Eligible families were consented, interviewed, and blood or sa (...truncated)