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Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk.pdf (632.83 kB)

Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk.

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posted on 2019-02-25, 16:33 authored by Kyle M. Walsh, Veryan Codd, Ivan V. Smirnov, Terri Rice, Paul A. Decker, Helen M. Hansen, Thomas Kollmeyer, Matthew L. Kosel, Annette M. Molinaro, Lucie S. McCoy, Paige M. Bracci, Belinda S. Cabriga, Melike Pekmezci, Shichun Zheng, Joseph L. Wiemels, Alexander R. Pico, Tarik Tihan, Mitchell S. Berger, Susan M. Chang, Michael D. Prados, Daniel H. Lachance, Brian Patrick O'Neill, Hugues Sicotte, Jeanette E. Eckel-Passow, ENGAGE Consortium Telomere Group, Pim van der Harst, John K. Wiencke, Nilesh J. Samani, Robert B. Jenkins, Margaret R. Wrensch
Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.


Work at UCSF was supported by the US National Institutes of Health (grants R25CA112355, R01CA52689, P50CA097257, R01CA126831 and R01CA139020), as well as by the National Brain Tumor Foundation, the UCSF Lewis Chair in Brain Tumor Research, the UCSF Robert Magnin Newman chair in Neuro-Oncology and donations from the families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper and William Martinusen. Work at the Mayo Clinic was supported by the US National Institutes of Health (grants P50CA108961 and P30CA15083), the National Institute of Neurological Disorders and Stroke (grant RC1NS068222Z), the Bernie and Edith Waterman Foundation, and the Ting Tsung and Wei Fong Chao Family Foundation. Work at the University of Leicester was undertaken under the European Union Framework Programme 7 ENGAGE Project (HEALTH-F4-2007-201413). V.C. and N.J.S. are supported by the British Heart Foundation. This project was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, US National Institutes of Health, through UCSF Clinical and Translational Science Institute grant UL1RR024131. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the US National Institutes of Health. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; by the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California and contract HHSN261201000034C awarded to the Public Health Institute; and by the Centers for Disease Control and Prevention National Program of Cancer Registries, under agreement U58DP003862-



Nature Genetics, 2014, 46 (7), pp. 731-735

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