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

Linda Kachuri; Olli Saarela; Stig Egil Bojesen; George Davey Smith; Geoffrey Liu; Maria Teresa Landi; Neil E. Caporaso; David C. Christiani; Mattias Johansson; Salvatore Panico; Kim Overvad; Antonia Trichopoulou; Paolo Vineis; Ghislaine Scelo; David Zaridze; Xifeng Wu; Demetrius Albanes; Brenda Diergaarde; Pagona Lagiou; Gary J. MacFarlane; Melinda C. Aldrich; Adonina Tardón; Gad Rennert; Andrew F. Olshan; Mark C. Weissler; Chu Chen; Gary E. Goodman; Jennifer A. Doherty; Andrew R. Ness; Heike Bickeböller; H.-Erich Wichmann; Angela Risch; John K. Field; M. Dawn Teare; Lambertus A. Kiemeney; Erik H.F.M. van der Heijden; June C. Carroll; Aage Haugen; Shanbeh Zienolddiny; Vidar Skaug; Victor Wünsch-Filho; Eloiza H. Tajara; Raquel Ayoub Moysés; Fabio Daumas Nunes; Stephen Lam; Jose Eluf-Neto; Martin Lacko; Wilbert H. M. Peters; Loic Le Marchand; Eric J. Duell; Angeline S. Andrew; Silvia Franceschi; Matthew B. Schabath; Jonas Manjer; Susanne Arnold; Philip Lazarus; Anush Mukeriya; Beata Swiatkowska; Vladimir Janout; Ivana Holcatova; Jelena Stojsic; Dana Mates; Jolanta Lissowska; Stefania Boccia; Corina Lesseur; Xuchen Zong; James D. Mckay; Paul Brennan; Christopher I. Amos; Rayjean J. Hung

doi:10.1093/ije/dyy140

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

Linda Kachuri, Olli Saarela, Stig Egil Bojesen, George Davey Smith, Geoffrey Liu, Maria Teresa Landi, Neil E. Caporaso, David C. Christiani, Mattias Johansson, Salvatore Panico, Kim Overvad, Antonia Trichopoulou, Paolo Vineis, Ghislaine Scelo, David Zaridze, Xifeng Wu, Demetrius Albanes, Brenda Diergaarde, Pagona Lagiou, Gary J. MacFarlaneMelinda C. Aldrich, Adonina Tardón, Gad Rennert, Andrew F. Olshan, Mark C. Weissler, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, Andrew R. Ness, Heike Bickeböller, H.-Erich Wichmann, Angela Risch, John K. Field, M. Dawn Teare, Lambertus A. Kiemeney, Erik H.F.M. van der Heijden, June C. Carroll, Aage Haugen, Shanbeh Zienolddiny, Vidar Skaug, Victor Wünsch-Filho, Eloiza H. Tajara, Raquel Ayoub Moysés, Fabio Daumas Nunes, Stephen Lam, Jose Eluf-Neto, Martin Lacko, Wilbert H. M. Peters, Loic Le Marchand, Eric J. Duell, Angeline S. Andrew, Silvia Franceschi, Matthew B. Schabath, Jonas Manjer, Susanne Arnold, Philip Lazarus, Anush Mukeriya, Beata Swiatkowska, Vladimir Janout, Ivana Holcatova, Jelena Stojsic, Dana Mates, Jolanta Lissowska, Stefania Boccia, Corina Lesseur, Xuchen Zong, James D. Mckay, Paul Brennan, Christopher I. Amos, Rayjean J. Hung (Corresponding Author)

Research output: Contribution to journal › Article › peer-review

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Abstract

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 (16396 cases, 13013 controls) and head and neck cancer (4415 cases, 5013 controls) using 8 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 (OR=1.41, 95% 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 etiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

Original language	English
Pages (from-to)	751-766
Number of pages	16
Journal	International Journal of Epidemiology
Volume	48
Issue number	3
Early online date	28 Jul 2018
DOIs	https://doi.org/10.1093/ije/dyy140
Publication status	Published - 2019

Bibliographical note

L.K. is a fellow in the Canadian Institutes of Health Research (CIHR) Strategic Training in Advanced Genetic Epidemiology (STAGE) programme and is supported by the CIHR Doctoral Research Award from the Frederick Banting and Charles Best Canada Graduate Scholarships (GSD-137441). Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by the National Institutes of Health (U19-CA148127, CA148127S1). Genotyping for the TRICL-ILCCO OncoArray was supported by in-kind genotyping at Centre for Inherited Disease Research (CIDR) (26820120008i-0–6800068-1). Genotyping for the Head and Neck Cancer OncoArray performed at CIDR was funded by the US National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780–0. CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03–0365 and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02–67 and FICYT IB09–133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health (NIH)/National Cancer Institute (NCI): UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989 (PI Doherty). The Liverpool Lung Project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578 and CA074386. The Multiethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464 and CA148127. The work performed in MSH-PMH study was supported by the Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997) and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Dr Melinda Aldrich is supported by the by NIH/National Cancer Institute 5K07CA172294. The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Kentucky Lung Cancer Research Initiative (KLCRI) was supported by the Department of Defense (Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program) under award number: 10153006 (W81XWH-11–1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The research undertaken by M.D.T., L.V.W. and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The Tampa study was funded by Public Health Service grants P01-CA68384 and R01-DE13158 from the National Institutes of Health. The University of Pittsburgh head and neck cancer case–control study is supported by US National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grants 04/12054–9 and 10/51168–0). The authors thank all the members of the GENCAPO team. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707–10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework programme (QLK1– 2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) awards IG 2011 10491 and IG 2013 14220 to S.B. and by Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97–0222), with additional funding from Fondo para la Investigación Científica y Tecnológica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768–2). The IARC Central Europe study was supported by the European Commission’s INCO-COPERNICUS Program (IC15-CT98–0332), US NIH/National Cancer Institute grant CA92039 and World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662 and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer.

Keywords

lung cancer
telomere length
chromosome 5p15.33
Mendelian randomization
mediation analysis
TERT
Mendelian Randomization
METAANALYSIS
SUSCEPTIBILITY LOCI
EXTENSION
GENETIC-VARIANTS
IDENTIFICATION
CHALLENGES
NEVER SMOKERS
DYSFUNCTION
EPIDEMIOLOGY
GENOME-WIDE ASSOCIATION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Accepted Manuscript
This is a pre-copyedited, author-produced version of an article accepted for publication in International Journal of Epidemiology following peer review. The version of record Linda Kachuri, Olli Saarela, Stig Egil Bojesen, et al. Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers, International Journal of Epidemiology, Volume 48, Issue 3, June 2019, Pages 751–766., is available online at: https://academic.oup.com/ije/article/48/3/751/5061128. doi: https://doi.org/10.1093/ije/dyy140
Accepted author manuscript, 0.99 MBLicence: Unspecified

Cite this

Kachuri, L., Saarela, O., Bojesen, S. E., Smith, G. D., Liu, G., Landi, M. T., Caporaso, N. E., Christiani, D. C., Johansson, M., Panico, S., Overvad, K., Trichopoulou, A., Vineis, P., Scelo, G., Zaridze, D., Wu, X., Albanes, D., Diergaarde, B., Lagiou, P., ... Hung, R. J. (2019). Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers. International Journal of Epidemiology, 48(3), 751-766. https://doi.org/10.1093/ije/dyy140

Kachuri, L, Saarela, O, Bojesen, SE, Smith, GD, Liu, G, Landi, MT, Caporaso, NE, Christiani, DC, Johansson, M, Panico, S, Overvad, K, Trichopoulou, A, Vineis, P, Scelo, G, Zaridze, D, Wu, X, Albanes, D, Diergaarde, B, Lagiou, P, MacFarlane, GJ, Aldrich, MC, Tardón, A, Rennert, G, Olshan, AF, Weissler, MC, Chen, C, Goodman, GE, Doherty, JA, Ness, AR, Bickeböller, H, Wichmann, H-E, Risch, A, Field, JK, Teare, MD, Kiemeney, LA, van der Heijden, EHFM, Carroll, JC, Haugen, A, Zienolddiny, S, Skaug, V, Wünsch-Filho, V, Tajara, EH, Moysés, RA, Nunes, FD, Lam, S, Eluf-Neto, J, Lacko, M, Peters, WHM, Le Marchand, L, Duell, EJ, Andrew, AS, Franceschi, S, Schabath, MB, Manjer, J, Arnold, S, Lazarus, P, Mukeriya, A, Swiatkowska, B, Janout, V, Holcatova, I, Stojsic, J, Mates, D, Lissowska, J, Boccia, S, Lesseur, C, Zong, X, Mckay, JD, Brennan, P, Amos, CI & Hung, RJ 2019, 'Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers', International Journal of Epidemiology, vol. 48, no. 3, pp. 751-766. https://doi.org/10.1093/ije/dyy140

@article{aeb9b2a6befc453587be14b7a0bb5c81,

title = "Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers",

abstract = "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 (16396 cases, 13013 controls) and head and neck cancer (4415 cases, 5013 controls) using 8 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 (OR=1.41, 95% 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 etiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci. ",

keywords = "lung cancer, telomere length, chromosome 5p15.33, Mendelian randomization, mediation analysis, TERT, Mendelian Randomization, METAANALYSIS, SUSCEPTIBILITY LOCI, EXTENSION, GENETIC-VARIANTS, IDENTIFICATION, CHALLENGES, NEVER SMOKERS, DYSFUNCTION, EPIDEMIOLOGY, GENOME-WIDE ASSOCIATION",

author = "Linda Kachuri and Olli Saarela and Bojesen, {Stig Egil} and Smith, {George Davey} and Geoffrey Liu and Landi, {Maria Teresa} and Caporaso, {Neil E.} and Christiani, {David C.} and Mattias Johansson and Salvatore Panico and Kim Overvad and Antonia Trichopoulou and Paolo Vineis and Ghislaine Scelo and David Zaridze and Xifeng Wu and Demetrius Albanes and Brenda Diergaarde and Pagona Lagiou and MacFarlane, {Gary J.} and Aldrich, {Melinda C.} and Adonina Tard{\'o}n and Gad Rennert and Olshan, {Andrew F.} and Weissler, {Mark C.} and Chu Chen and Goodman, {Gary E.} and Doherty, {Jennifer A.} and Ness, {Andrew R.} and Heike Bickeb{\"o}ller and H.-Erich Wichmann and Angela Risch and Field, {John K.} and Teare, {M. Dawn} and Kiemeney, {Lambertus A.} and {van der Heijden}, {Erik H.F.M.} and Carroll, {June C.} and Aage Haugen and Shanbeh Zienolddiny and Vidar Skaug and Victor W{\"u}nsch-Filho and Tajara, {Eloiza H.} and Moys{\'e}s, {Raquel Ayoub} and Nunes, {Fabio Daumas} and Stephen Lam and Jose Eluf-Neto and Martin Lacko and Peters, {Wilbert H. M.} and {Le Marchand}, Loic and Duell, {Eric J.} and Andrew, {Angeline S.} and Silvia Franceschi and Schabath, {Matthew B.} and Jonas Manjer and Susanne Arnold and Philip Lazarus and Anush Mukeriya and Beata Swiatkowska and Vladimir Janout and Ivana Holcatova and Jelena Stojsic and Dana Mates and Jolanta Lissowska and Stefania Boccia and Corina Lesseur and Xuchen Zong and Mckay, {James D.} and Paul Brennan and Amos, {Christopher I.} and Hung, {Rayjean J.}",

note = "L.K. is a fellow in the Canadian Institutes of Health Research (CIHR) Strategic Training in Advanced Genetic Epidemiology (STAGE) programme and is supported by the CIHR Doctoral Research Award from the Frederick Banting and Charles Best Canada Graduate Scholarships (GSD-137441). Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by the National Institutes of Health (U19-CA148127, CA148127S1). Genotyping for the TRICL-ILCCO OncoArray was supported by in-kind genotyping at Centre for Inherited Disease Research (CIDR) (26820120008i-0–6800068-1). Genotyping for the Head and Neck Cancer OncoArray performed at CIDR was funded by the US National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780–0. CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03–0365 and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02–67 and FICYT IB09–133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud P{\'u}blica. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health (NIH)/National Cancer Institute (NCI): UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989 (PI Doherty). The Liverpool Lung Project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578 and CA074386. The Multiethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464 and CA148127. The work performed in MSH-PMH study was supported by the Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997) and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center{\textquoteright}s BioVU, which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Dr Melinda Aldrich is supported by the by NIH/National Cancer Institute 5K07CA172294. The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Kentucky Lung Cancer Research Initiative (KLCRI) was supported by the Department of Defense (Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program) under award number: 10153006 (W81XWH-11–1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The research undertaken by M.D.T., L.V.W. and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The Tampa study was funded by Public Health Service grants P01-CA68384 and R01-DE13158 from the National Institutes of Health. The University of Pittsburgh head and neck cancer case–control study is supported by US National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Funda{\c c}{\~a}o de Amparo {\`a} Pesquisa do Estado de S{\~a}o Paulo (FAPESP; grants 04/12054–9 and 10/51168–0). The authors thank all the members of the GENCAPO team. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707–10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission{\textquoteright}s fifth framework programme (QLK1– 2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) awards IG 2011 10491 and IG 2013 14220 to S.B. and by Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97–0222), with additional funding from Fondo para la Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (Argentina) and the Funda{\c c}{\~a}o de Amparo {\`a} Pesquisa do Estado de S{\~a}o Paulo (01/01768–2). The IARC Central Europe study was supported by the European Commission{\textquoteright}s INCO-COPERNICUS Program (IC15-CT98–0332), US NIH/National Cancer Institute grant CA92039 and World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662 and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer.",

year = "2019",

doi = "10.1093/ije/dyy140",

language = "English",

volume = "48",

pages = "751--766",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "OXFORD UNIV PRESS",

number = "3",

}

TY - JOUR

T1 - Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

AU - Kachuri, Linda

AU - Saarela, Olli

AU - Bojesen, Stig Egil

AU - Smith, George Davey

AU - Liu, Geoffrey

AU - Landi, Maria Teresa

AU - Caporaso, Neil E.

AU - Christiani, David C.

AU - Johansson, Mattias

AU - Panico, Salvatore

AU - Overvad, Kim

AU - Trichopoulou, Antonia

AU - Vineis, Paolo

AU - Scelo, Ghislaine

AU - Zaridze, David

AU - Wu, Xifeng

AU - Albanes, Demetrius

AU - Diergaarde, Brenda

AU - Lagiou, Pagona

AU - MacFarlane, Gary J.

AU - Aldrich, Melinda C.

AU - Tardón, Adonina

AU - Rennert, Gad

AU - Olshan, Andrew F.

AU - Weissler, Mark C.

AU - Chen, Chu

AU - Goodman, Gary E.

AU - Doherty, Jennifer A.

AU - Ness, Andrew R.

AU - Bickeböller, Heike

AU - Wichmann, H.-Erich

AU - Risch, Angela

AU - Field, John K.

AU - Teare, M. Dawn

AU - Kiemeney, Lambertus A.

AU - van der Heijden, Erik H.F.M.

AU - Carroll, June C.

AU - Haugen, Aage

AU - Zienolddiny, Shanbeh

AU - Skaug, Vidar

AU - Wünsch-Filho, Victor

AU - Tajara, Eloiza H.

AU - Moysés, Raquel Ayoub

AU - Nunes, Fabio Daumas

AU - Lam, Stephen

AU - Eluf-Neto, Jose

AU - Lacko, Martin

AU - Peters, Wilbert H. M.

AU - Le Marchand, Loic

AU - Duell, Eric J.

AU - Andrew, Angeline S.

AU - Franceschi, Silvia

AU - Schabath, Matthew B.

AU - Manjer, Jonas

AU - Arnold, Susanne

AU - Lazarus, Philip

AU - Mukeriya, Anush

AU - Swiatkowska, Beata

AU - Janout, Vladimir

AU - Holcatova, Ivana

AU - Stojsic, Jelena

AU - Mates, Dana

AU - Lissowska, Jolanta

AU - Boccia, Stefania

AU - Lesseur, Corina

AU - Zong, Xuchen

AU - Mckay, James D.

AU - Brennan, Paul

AU - Amos, Christopher I.

AU - Hung, Rayjean J.

N1 - L.K. is a fellow in the Canadian Institutes of Health Research (CIHR) Strategic Training in Advanced Genetic Epidemiology (STAGE) programme and is supported by the CIHR Doctoral Research Award from the Frederick Banting and Charles Best Canada Graduate Scholarships (GSD-137441). Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by the National Institutes of Health (U19-CA148127, CA148127S1). Genotyping for the TRICL-ILCCO OncoArray was supported by in-kind genotyping at Centre for Inherited Disease Research (CIDR) (26820120008i-0–6800068-1). Genotyping for the Head and Neck Cancer OncoArray performed at CIDR was funded by the US National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780–0. CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03–0365 and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02–67 and FICYT IB09–133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health (NIH)/National Cancer Institute (NCI): UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989 (PI Doherty). The Liverpool Lung Project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578 and CA074386. The Multiethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464 and CA148127. The work performed in MSH-PMH study was supported by the Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997) and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Dr Melinda Aldrich is supported by the by NIH/National Cancer Institute 5K07CA172294. The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Kentucky Lung Cancer Research Initiative (KLCRI) was supported by the Department of Defense (Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program) under award number: 10153006 (W81XWH-11–1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The research undertaken by M.D.T., L.V.W. and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The Tampa study was funded by Public Health Service grants P01-CA68384 and R01-DE13158 from the National Institutes of Health. The University of Pittsburgh head and neck cancer case–control study is supported by US National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grants 04/12054–9 and 10/51168–0). The authors thank all the members of the GENCAPO team. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707–10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework programme (QLK1– 2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) awards IG 2011 10491 and IG 2013 14220 to S.B. and by Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97–0222), with additional funding from Fondo para la Investigación Científica y Tecnológica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768–2). The IARC Central Europe study was supported by the European Commission’s INCO-COPERNICUS Program (IC15-CT98–0332), US NIH/National Cancer Institute grant CA92039 and World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662 and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer.

PY - 2019

Y1 - 2019

N2 - 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 (16396 cases, 13013 controls) and head and neck cancer (4415 cases, 5013 controls) using 8 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 (OR=1.41, 95% 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 etiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

AB - 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 (16396 cases, 13013 controls) and head and neck cancer (4415 cases, 5013 controls) using 8 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 (OR=1.41, 95% 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 etiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

KW - lung cancer

KW - telomere length

KW - chromosome 5p15.33

KW - Mendelian randomization

KW - mediation analysis

KW - TERT

KW - Mendelian Randomization

KW - METAANALYSIS

KW - SUSCEPTIBILITY LOCI

KW - EXTENSION

KW - GENETIC-VARIANTS

KW - IDENTIFICATION

KW - CHALLENGES

KW - NEVER SMOKERS

KW - DYSFUNCTION

KW - EPIDEMIOLOGY

KW - GENOME-WIDE ASSOCIATION

UR - http://www.mendeley.com/research/mendelian-randomization-mediation-analysis-leukocyte-telomere-length-risk-lung-head-neck-cancers

UR - http://www.scopus.com/inward/record.url?scp=85068783172&partnerID=8YFLogxK

U2 - 10.1093/ije/dyy140

DO - 10.1093/ije/dyy140

M3 - Article

SN - 0300-5771

VL - 48

SP - 751

EP - 766

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 3

ER -

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

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