Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Adenocarcinoma of Lung / epidemiology Aged Aged, 80 and over Carcinoma, Squamous Cell / epidemiology Chromosomes, Human, Pair 5 / genetics Female Head and Neck Neoplasms / epidemiology Humans Leukocytes / metabolism Lung Neoplasms / epidemiology Male Mendelian Randomization Analysis Middle Aged Squamous Cell Carcinoma of Head and Neck / epidemiology Telomere / metabolism Telomere Homeostasis / genetics
Mendelian Randomization TERT chromosome 5p15.33 lung cancer mediation analysis telomere length

Journal

International journal of epidemiology
ISSN: 1464-3685
Titre abrégé: Int J Epidemiol
Pays: England
ID NLM: 7802871

Informations de publication

Date de publication:
01 06 2019
Historique:
accepted: 14 06 2018
pubmed: 31 7 2018
medline: 2 4 2020
entrez: 31 7 2018
Statut: ppublish

Résumé

Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

Sections du résumé

BACKGROUND
Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.
METHODS
We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.
RESULTS
The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.
CONCLUSIONS
Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

Identifiants

DOI: 10.1093/ije/dyy140 PMID: 30059977 PMC: PMC6659464
pubmed: 30059977
pii: 5061128
doi: 10.1093/ije/dyy140
pmc: PMC6659464
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

751-766

Subventions

Organisme : NCI NIH HHS
ID : U01 CA063673
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA119997
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000117
Pays : United States
Organisme : Medical Research Council
ID : MR/L01341X/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P50 CA097190
Pays : United States
Organisme : Department of Health
ID : RP-PG-0707-10034
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA111703
Pays : United States
Organisme : Medical Research Council
ID : G0902313
Pays : United Kingdom
Organisme : CIHR
ID : GSD-137441
Pays : Canada
Organisme : NCATS NIH HHS
ID : UL1 TR000445
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197449
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167462
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA203654
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : K07 CA172294
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : Cancer Research UK
ID : C18281/A19169
Pays : United Kingdom
Organisme : NCRR NIH HHS
ID : P20 RR018787
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA151989
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148127
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA167462
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA177558
Pays : United States

Informations de copyright

© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

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Auteurs

Linda Kachuri (L)

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Olli Saarela (O)

Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Stig Egil Bojesen (SE)

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

George Davey Smith (G)

Population Health Science, Bristol Medical School, MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Geoffrey Liu (G)

Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
Ontario Cancer Institute, Princess Margaret Cancer Center, Toronto, Ontario, Canada.

Maria Teresa Landi (MT)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Neil E Caporaso (NE)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

David C Christiani (DC)

Departments of Epidemiology and Environmental Health, Harvard TH Chan School of Public Health, Boston, MA, USA.
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Mattias Johansson (M)

International Agency for Research on Cancer, Lyon, France.

Salvatore Panico (S)

Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.

Kim Overvad (K)

Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.

Antonia Trichopoulou (A)

Hellenic Health Foundation, and WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Athens, Greece.
Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Paolo Vineis (P)

MRC/PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Ghislaine Scelo (G)

International Agency for Research on Cancer, Lyon, France.

David Zaridze (D)

Department of Epidemiology and Prevention, Russian N.N.Blokhin Cancer Research Centre, Moscow, Russian Federation.

Xifeng Wu (X)

Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Demetrius Albanes (D)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Brenda Diergaarde (B)

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Pagona Lagiou (P)

Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Gary J Macfarlane (GJ)

The Institute of Applied Health Sciences, School of Medicine, University of Aberdeen, Aberdeen, UK.

Melinda C Aldrich (MC)

Department of Thoracic Surgery and Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.

Adonina Tardón (A)

Faculty of Medicine, University of Oviedo and CIBERESP, Campus del Cristo, Oviedo, Spain.

Gad Rennert (G)

Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.

Andrew F Olshan (AF)

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Mark C Weissler (MC)

Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Chu Chen (C)

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Gary E Goodman (GE)

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Jennifer A Doherty (JA)

Department of Population Health Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Andrew R Ness (AR)

School of Oral and Dental Sciences, University of Bristol, Bristol, UK.

Heike Bickeböller (H)

Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Germany.

H-Erich Wichmann (HE)

Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.
Institute of Medical Statistics and Epidemiology, Technical University, Munich, Germany.

Angela Risch (A)

Division of Epigenomics & Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.

John K Field (JK)

Roy Castle Lung Cancer Research Programme, University of Liverpool Cancer Research Centre Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

M Dawn Teare (MD)

School of Health and Related Research, University of Sheffield, Sheffield, UK.

Lambertus A Kiemeney (LA)

Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.

Erik H F M van der Heijden (EHFM)

Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.

June C Carroll (JC)

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.

Aage Haugen (A)

The National Institute of Occupational Health, Oslo, Norway.

Shanbeh Zienolddiny (S)

The National Institute of Occupational Health, Oslo, Norway.

Vidar Skaug (V)

The National Institute of Occupational Health, Oslo, Norway.

Victor Wünsch-Filho (V)

Faculdade de Saúde Pública, Universidade de São Paulo, Brazil.

Eloiza H Tajara (EH)

Department of Molecular Biology, School of Medicine of São José do Rio Preto, São José do Rio Preto, Brazil.

Raquel Ayoub Moysés (R)

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Disciplina de Cirurgia de Cabeça e Pescoço (LIM28), São Paulo, Brasil.

Fabio Daumas Nunes (F)

Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo, Brazil.

Stephen Lam (S)

BC Cancer Agency, Vancouver, BC, Canada.

Jose Eluf-Neto (J)

Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Martin Lacko (M)

Department of Otorhinolaryngology, Head and Neck Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.

Wilbert H M Peters (WHM)

Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Loïc Le Marchand (L)

Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.

Eric J Duell (EJ)

Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.

Angeline S Andrew (AS)

Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.

Silvia Franceschi (S)

International Agency for Research on Cancer, Lyon, France.

Matthew B Schabath (MB)

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Jonas Manjer (J)

Skåne University Hospital, Lund University, Lund, Sweden.

Susanne Arnold (S)

Markey Cancer Center, University of Kentucky, Lexington, KY, USA.

Philip Lazarus (P)

College of Pharmacy, Washington State University, Spokane, WA, USA.

Anush Mukeriya (A)

Department of Epidemiology and Prevention, Russian N.N.Blokhin Cancer Research Centre, Moscow, Russian Federation.

Beata Swiatkowska (B)

Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.

Vladimir Janout (V)

Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic.

Ivana Holcatova (I)

Institute of Public Health and Preventive Medicine, Second Faculty of Medicine, Charles University, Prague, Czech Republic.

Jelena Stojsic (J)

Department of Thoracopulmonary Pathology, Service of Pathology, Clinical Center of Serbia, Belgrade, Serbia.

Dana Mates (D)

National Institute of Public Health, Bucharest, Romania.

Jolanta Lissowska (J)

Department of Cancer Epidemiology and Prevention, Cancer Center Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland.

Stefania Boccia (S)

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italia.
Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.

Corina Lesseur (C)

International Agency for Research on Cancer, Lyon, France.
Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Xuchen Zong (X)

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.

James D McKay (JD)

International Agency for Research on Cancer, Lyon, France.

Paul Brennan (P)

International Agency for Research on Cancer, Lyon, France.

Christopher I Amos (CI)

Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.

Rayjean J Hung (RJ)

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

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Classifications MeSH

questionsmedicales.fr › Tumeurs › Tumeurs par siège › Tumeurs du thorax › Adénocarcinome pulmonaire › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Tumeurs épidermoïdes › Carcinome épidermoïde › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Chromosomes › Chromosomes de mammifère › Chromosomes humains › Chromosomes humains 4-5 › Chromosomes humains de la paire 5 › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Tumeurs › Tumeurs par siège › Tumeurs de la tête et du cou › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Techniques d'investigation › Analyse de randomisation mendélienne › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Tumeurs › Tumeurs par siège › Tumeurs de la tête et du cou › Carcinome épidermoïde de la tête et du cou › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Télomère › Mendelian Randomization and mediation analysis...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Division cellulaire › Homéostasie des télomères › Mendelian Randomization and mediation analysis...