title: Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.
abstract: Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.|Program in Neurologic Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.|National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors.forename: Veryan
authors.initials: V
authors.lastname: Codd
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Terri
authors.initials: T
authors.lastname: Rice
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.|National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Smirnov
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Lucie S
authors.initials: LS
authors.lastname: McCoy
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Hansen
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Elhauge
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Juhi
authors.initials: J
authors.lastname: Ojha
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Francis
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Nils R
authors.initials: NR
authors.lastname: Madsen
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco , California, USA.
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.affiliation: Gladstone Institutes, San Francisco, California, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Pico
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.|Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco , California, USA.|Institute for Human Genetics, University of California, San Francisco, San Francisco , California, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.|National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.|Institute for Human Genetics, University of California, San Francisco, San Francisco , California, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.|Institute for Human Genetics, University of California, San Francisco, San Francisco , California, USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D005910:Glioma / Q000235:genetics*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016615:Telomere / Q000235:genetics*
keywords: CST complex; glioma; single nucleotide polymorphism; telomerase; telomere