. 2015 Dec 15;6(40):42468-77.

doi: 10.18632/oncotarget.6468.

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

Kyle M Walsh^{1

2}, Veryan Codd^{3

4}, Terri Rice¹, Christopher P Nelson^{3

4}, Ivan V Smirnov⁵, Lucie S McCoy¹, Helen M Hansen¹, Edward Elhauge¹, Juhi Ojha¹, Stephen S Francis⁵, Nils R Madsen¹, Paige M Bracci⁶, Alexander R Pico⁷, Annette M Molinaro⁵, Tarik Tihan⁸, Mitchel S Berger⁵, Susan M Chang⁵, Michael D Prados⁵, Robert B Jenkins⁹, Joseph L Wiemels^{1

6

10}; ENGAGE Consortium Telomere Group; Nilesh J Samani^{3

4}, John K Wiencke^{1

10}, Margaret R Wrensch^{1

10}

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 Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
² Program in Neurologic Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
³ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
⁴ National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
⁶ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco , California, USA.
⁷ Gladstone Institutes, San Francisco, California, USA.
⁸ Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
¹⁰ Institute for Human Genetics, University of California, San Francisco, San Francisco , California, USA.

PMID: 26646793
PMCID: PMC4767445
DOI: 10.18632/oncotarget.6468

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

Kyle M Walsh et al. Oncotarget. 2015.

. 2015 Dec 15;6(40):42468-77.

doi: 10.18632/oncotarget.6468.

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 Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
² Program in Neurologic Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
³ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
⁴ National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
⁶ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco , California, USA.
⁷ Gladstone Institutes, San Francisco, California, USA.
⁸ Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
¹⁰ Institute for Human Genetics, University of California, San Francisco, San Francisco , California, USA.

PMID: 26646793
PMCID: PMC4767445
DOI: 10.18632/oncotarget.6468

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.

Keywords: CST complex; glioma; single nucleotide polymorphism; telomerase; telomere.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

Figures

Figure 1. Boxplots comparing genotypically-estimated leukocyte telomere length in glioma patients and controls from discovery analyses (652 glioma patients, 3735 controls), replication analyses (478 glioma patients, 2559 controls), and combined analyses (1130 glioma patients, 6294 controls); glioma cases from the UCSF Adult Glioma Study (AGS) and TCGA, and controls from AGS, Illumina iControls and Wellcome-Trust
P-values are adjusted for the first two ancestry-informative principal components and, in the combined analysis, for genotyping platform.

**Figure 2. Effect of increasing septile of genotypically-estimated leukocyte telomere length on glioma risk in combined discovery and replication datasets**
The odds ratios are relative to the median (fourth) septile. Vertical bars correspond to 95% confidence intervals. Septiles were defined among controls and ranges were: septile one (115bp-403bp), septile two (404bp-467bp), septile three (468bp-523bp), septile four (524bp-567bp), septile five (568bp-616bp), septile six (617bp-684bp), septile seven (685bp-1008bp).

**Figure 3. Forest plot showing the effect of alleles associated with longer leukocyte telomere length on glioma risk**
Allelic odds ratios are plotted with 95% confidence intervals. The overall estimate is for the combined effect of all 8 SNPs, where the odds ratio relates to the change in glioma risk for one standard deviation increase in genotypically-estimated leukocyte telomere length. Odds ratios are based on combined data from 1130 glioma patients and 6294 controls.

See this image and copyright information in PMC

References

1. Wrensch M, Jenkins RB, Chang JS, Yeh RF, Xiao Y, Decker PA, Ballman KV, Berger M, Buckner JC, Chang S, Giannini C, Halder C, Kollmeyer TM, Kosel ML, LaChance DH, McCoy L, et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet. 2009;41:905–908. - PMC - PubMed
1. Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, Simon M, Marie Y, Boisselier B, Delattre JY, Hoang-Xuan K, El Hallani S, Idbaih A, Zelenika D, Andersson U, Henriksson R, et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet. 2009;41:899–904. - PMC - PubMed
1. Walsh KM, Codd V, Smirnov IV, Rice T, Decker PA, Hansen HM, Kollmeyer T, Kosel ML, Molinaro AM, McCoy LS, Bracci PM, Cabriga BS, Pekmezci M, Zheng S, Wiemels JL, Pico AR, et al. Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nat Genet. 2014;46:731–735. - PMC - PubMed
1. Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL, Hottenga JJ, Fischer K, Esko T, Surakka I, Broer L, Nyholt DR, Mateo Leach I, Salo P, Hagg S, Matthews MK, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013;45:422–427. 427e421-422. - PMC - PubMed
1. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T. Mammalian telomeres end in a large duplex loop. Cell. 1999;97:503–514. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

Collaborators

Affiliations

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical