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Hum Mol Genet. 2015 Sep 15;24(18):5356-66. doi: 10.1093/hmg/ddv252. Epub 2015 Jul 2.

Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.

Author information

1
Department of Public Health Sciences.
2
Section of Biostatistics and Epidemiology.
3
Department of Public Health and Primary Care.
4
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
5
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
6
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
7
Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
8
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
9
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
10
Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
11
Division of Epigenomics and Cancer Risk Factors, DKFZ, German Cancer Research Center, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
12
International Agency for Research on Cancer, Lyon, France.
13
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
14
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Public Health Service, Bethesda, MD, USA.
15
Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
16
The Institute of Cancer Research, Sutton, UK.
17
The Institute of Cancer Research, Sutton, UK, Royal Marsden National Health Service (NHS) Foundation Trust, London and Sutton, UK.
18
Warwick Medical School, University of Warwick, Coventry, UK, Institute of Population Health, University of Manchester, Manchester, UK.
19
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
20
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
21
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
22
Molecular Genetics/Laboratory Medicine and Pathobiology, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
23
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia.
24
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
25
Cancer Prevention Institute of California, Fremont, CA, USA, Stanford University School of Medicine, Stanford, CA, USA.
26
Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, NC, USA.
27
Kreftregisteret, Cancer Registry of Norway, Oslo, Norway.
28
Stanford University School of Medicine, Stanford, CA, USA.
29
USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
30
Ontario Cancer Genetics Network, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada, Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
31
Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
32
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
33
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
34
Ontario Institute for Cancer Research, Toronto, ON, Canada.
35
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
36
Department of Family Medicine and Community Health, Case Western Reserve University, Cleveland, OH, USA and.
37
Discipline of Genetics, Faculty of Medicine, Memorial University, Newfoundland and Labrador, Canada.
38
Department of Public Health Sciences, Center for Cancer Epidemiology and Prevention, Department of Medicine, Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
39
Department of Public Health Sciences, Center for Cancer Epidemiology and Prevention, Department of Human Genetics, The University of Chicago, Chicago, IL, USA, brandonpierce@uchicago.edu.

Abstract

Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

PMID:
26138067
PMCID:
PMC4550826
DOI:
10.1093/hmg/ddv252
[Indexed for MEDLINE]
Free PMC Article

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