Comparative Study

. 2014 Jul;46(7):731-5.

doi: 10.1038/ng.3004. Epub 2014 Jun 8.

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

Kyle M Walsh¹, Veryan Codd², Ivan V Smirnov³, Terri Rice⁴, Paul A Decker⁵, Helen M Hansen⁴, Thomas Kollmeyer⁶, Matthew L Kosel⁵, Annette M Molinaro³, Lucie S McCoy⁴, Paige M Bracci⁷, Belinda S Cabriga⁴, Melike Pekmezci⁸, Shichun Zheng⁴, Joseph L Wiemels⁹, Alexander R Pico¹⁰, Tarik Tihan⁸, Mitchell S Berger³, Susan M Chang³, Michael D Prados³, Daniel H Lachance¹¹, Brian Patrick O'Neill¹¹, Hugues Sicotte⁵, Jeanette E Eckel-Passow⁵; ENGAGE Consortium Telomere Group; Pim van der Harst¹², John K Wiencke¹³, Nilesh J Samani², Robert B Jenkins⁶, Margaret R Wrensch¹³

Collaborators, Affiliations

Collaborators

ENGAGE Consortium Telomere Group:
Veryan Codd, Christopher P Nelson, Eva Albrecht, Massimo Mangino, Joris Deelen, Jessica L Buxton, Jouke Jan Hottenga, Krista Fischer, Tõnu Esko, Ida Surakka, Linda Broer, Dale R Nyholt, Irene Mateo Leach, Perttu Salo, Sara Hägg, Mary K Matthews, Jutta Palmen, Giuseppe D Norata, Paul F O'Reilly, Danish Saleheen, Najaf Amin, Anthony J Balmforth, Marian Beekman, Rudolf A de Boer, Stefan Böhringer, Peter S Braund, Paul R Burton, Anton J M de Craen, Matthew Denniff, Yanbin Dong, Konstantinos Douroudis, Elena Dubinina, Johan G Eriksson, Katia Garlaschelli, Dehuang Guo, Anna-Liisa Hartikainen, Anjali K Henders, Jeanine J Houwing-Duistermaat, Laura Kananen, Lennart C Karssen, Johannes Kettunen, Norman Klopp, Vasiliki Lagou, Elisabeth M van Leeuwen, Pamela A Madden, Reedik Mägi, Patrik K E Magnusson, Satu Männistö, Mark I McCarthy, Sarah E Medland, Evelin Mihailov, Grant W Montgomery, Ben A Oostra, Aarno Palotie, Annette Peters, Helen Pollard, Anneli Pouta, Inga Prokopenko, Samuli Ripatti, Veikko Salomaa, H Eka D Suchiman, Ana M Valdes, Niek Verweij, Ana Viñuela, Xiaoling Wang, H-Erich Wichmann, Elisabeth Widen, Gonneke Willemsen, Margaret J Wright, Kai Xia, Xiangjun Xiao, Dirk J van Veldhuisen, Alberico L Catapano, Martin D Tobin, Alistair S Hall, Alexandra I F Blakemore, Wiek H van Gilst, Haidong Zhu, Jeanette Erdmann, Muredach P Reilly, Sekar Kathiresan, Heribert Schunkert, Philippa J Talmud, Nancy L Pedersen, Markus Perola, Willem Ouwehand, Jaakko Kaprio, Nicholas G Martin, Cornelia M van Duijn, Iiris Hovatta, Christian Gieger, Andres Metspalu, Dorret I Boomsma, Marjo-Riitta Jarvelin, P Eline Slagboom, John R Thompson, Tim D Spector, Pim van der Harst, Nilesh J Samani

Affiliations

¹ 1] Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Program in Cancer Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
² 1] Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. [2] National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
³ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
⁴ Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
⁵ Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
⁷ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
⁸ Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
⁹ 1] Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. [3] Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
¹⁰ 1] Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Department of Bioinformatics, Gladstone Institutes, San Francisco, California, USA.
¹¹ Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
¹² 1] Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. [2] Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹³ 1] Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.

PMID: 24908248
PMCID: PMC4074274
DOI: 10.1038/ng.3004

Comparative Study

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

Kyle M Walsh et al. Nat Genet. 2014 Jul.

. 2014 Jul;46(7):731-5.

doi: 10.1038/ng.3004. Epub 2014 Jun 8.

Authors

Collaborators

ENGAGE Consortium Telomere Group:
Veryan Codd, Christopher P Nelson, Eva Albrecht, Massimo Mangino, Joris Deelen, Jessica L Buxton, Jouke Jan Hottenga, Krista Fischer, Tõnu Esko, Ida Surakka, Linda Broer, Dale R Nyholt, Irene Mateo Leach, Perttu Salo, Sara Hägg, Mary K Matthews, Jutta Palmen, Giuseppe D Norata, Paul F O'Reilly, Danish Saleheen, Najaf Amin, Anthony J Balmforth, Marian Beekman, Rudolf A de Boer, Stefan Böhringer, Peter S Braund, Paul R Burton, Anton J M de Craen, Matthew Denniff, Yanbin Dong, Konstantinos Douroudis, Elena Dubinina, Johan G Eriksson, Katia Garlaschelli, Dehuang Guo, Anna-Liisa Hartikainen, Anjali K Henders, Jeanine J Houwing-Duistermaat, Laura Kananen, Lennart C Karssen, Johannes Kettunen, Norman Klopp, Vasiliki Lagou, Elisabeth M van Leeuwen, Pamela A Madden, Reedik Mägi, Patrik K E Magnusson, Satu Männistö, Mark I McCarthy, Sarah E Medland, Evelin Mihailov, Grant W Montgomery, Ben A Oostra, Aarno Palotie, Annette Peters, Helen Pollard, Anneli Pouta, Inga Prokopenko, Samuli Ripatti, Veikko Salomaa, H Eka D Suchiman, Ana M Valdes, Niek Verweij, Ana Viñuela, Xiaoling Wang, H-Erich Wichmann, Elisabeth Widen, Gonneke Willemsen, Margaret J Wright, Kai Xia, Xiangjun Xiao, Dirk J van Veldhuisen, Alberico L Catapano, Martin D Tobin, Alistair S Hall, Alexandra I F Blakemore, Wiek H van Gilst, Haidong Zhu, Jeanette Erdmann, Muredach P Reilly, Sekar Kathiresan, Heribert Schunkert, Philippa J Talmud, Nancy L Pedersen, Markus Perola, Willem Ouwehand, Jaakko Kaprio, Nicholas G Martin, Cornelia M van Duijn, Iiris Hovatta, Christian Gieger, Andres Metspalu, Dorret I Boomsma, Marjo-Riitta Jarvelin, P Eline Slagboom, John R Thompson, Tim D Spector, Pim van der Harst, Nilesh J Samani

Affiliations

¹ 1] Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Program in Cancer Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
² 1] Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. [2] National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
³ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
⁴ Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
⁵ Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
⁷ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
⁸ Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
⁹ 1] Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. [3] Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
¹⁰ 1] Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Department of Bioinformatics, Gladstone Institutes, San Francisco, California, USA.
¹¹ Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
¹² 1] Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. [2] Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹³ 1] Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.

PMID: 24908248
PMCID: PMC4074274
DOI: 10.1038/ng.3004

Abstract

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.

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Figures

**Figure 1. SNP association plots for high-grade glioma risk and mean leukocyte telomere length at 3q26.2 (*TERC*), 5p15.33 (*TERT*), and 20q13.33 (*RTEL1*)**
Telomere associations (grey squares) are from the telomere length genome-wide association meta-analysis (N=37684). Glioma associations (red circles) are from the genome-wide discovery meta-analysis, combining data from the UCSF Adult Glioma Study, The Cancer Genome Atlas, and the Wellcome Trust Case-Control Consortium (N=1013 cases and 6595 controls). Red diamonds are from the combined glioma discovery and UCSF and Mayo Clinic replication analyses (1644 cases, 7736 controls).

**Figure 2. SNP association plots indicating the –log10P for association with high-grade glioma risk (y-axis) and mean leukocyte telomere length (x-axis)**
Colors correspond to whether the glioma risk allele is associated with longer (blue) or shorter (orange) leukocyte telomere length.

See this image and copyright information in PMC

References

1. Codd V, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013;45:422–7. 427e1–2. - PMC - PubMed
1. Stupp R, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66. - PubMed
1. Sanson M, et al. Chromosome 7p11. EGFR) variation influences glioma risk. Hum Mol Genet. 2011;20:2897–904. - PMC - PubMed
1. Shete S, et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet. 2009;41:899–904. - PMC - PubMed
1. Stacey SN, et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet. 2011;43:1098–103. - PMC - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources