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

Autor(es):Mostrar menos -

Kachuri, Linda ^{[1, 2]} ; Saarela, Olli ^[3] ; Bojesen, Stig Egil ^{[4, 5]} ; Smith, George Davey ^[6] ; Liu, Geoffrey ^{[2, 7]} ; Landi, Maria Teresa ^[8] ; Caporaso, Neil E. ^[8] ; Christiani, David C. ^{[9, 10, 11, 12]} ; Johansson, Mattias ^[13] ; Panico, Salvatore ^[14] ; Overvad, Kim ^[15] ; Trichopoulou, Antonia ^{[16, 17, 18]} ; Vineis, Paolo ^[19] ; Scelo, Ghislaine ^[13] ; Zaridze, David ^[20] ; Wu, Xifeng ^[21] ; Albanes, Demetrius ^[8] ; Diergaarde, Brenda ^[22] ; Lagiou, Pagona ^[16] ; Macfarlane, Gary J. ^[23] ; Aldrich, Melinda C. ^{[24, 25]} ; Tardon, Adonina ^{[26, 27]} ; Rennert, Gad ^{[28, 29]} ; Olshan, Andrew F. ^[30] ; Weissler, Mark C. ^[31] ; Chen, Chu ^[32] ; Goodman, Gary E. ^[32] ; Doherty, Jennifer A. ^[33] ; Ness, Andrew R. ^[34] ; Bickeboeller, Heike ^[35] ; Wichmann, H-Erich ^{[36, 37, 38]} ; Risch, Angela ^[39] ; Field, John K. ^[40] ; Teare, M. Dawn ^[41] ; Kiemeney, Lambertus A. ^[42] ; van der Heijden, Erik H. F. M. ^[42] ; Carroll, June C. ^[1] ; Haugen, Aage ^[43] ; Zienolddiny, Shanbeh ^[43] ; Skaug, Vidar ^[43] ; Wuensch-Filho, Victor ^[44] ; Tajara, Eloiza H. ^[45] ; Moyses, Raquel Ayoub ^[46] ; Nunes, Fabio Daumas ^[47] ; Lam, Stephen ^[48] ; Eluf-Neto, Jose ^[49] ; Lacko, Martin ^[50] ; Peters, Wilbert H. M. ^[51] ; Le Marchand, Loic ^[52] ; Duell, Eric J. ^[53] ; Andrew, Angeline S. ^[54] ; Franceschi, Silvia ^[13] ; Schabath, Matthew B. ^[55] ; Manjer, Jonas ^[56] ; Arnold, Susanne ^[57] ; Lazarus, Philip ^[58] ; Mukeriya, Anush ^[20] ; Swiatkowska, Beata ^[59] ; Janout, Vladimir ^[60] ; Holcatova, Ivana ^[61] ; Stojsic, Jelena ^[62] ; Mates, Dana ^[63] ; Lissowska, Jolanta ^[64] ; Boccia, Stefania ^{[65, 66]} ; Lesseur, Corina ^{[13, 67]} ; Zong, Xuchen ^[1] ; McKay, James D. ^[13] ; Brennan, Paul ^[13] ; Amos, Christopher I. ^[68] ; Hung, Rayjean J. ^{[1, 2]}

Afiliação do(s) autor(es):Mostrar menos -

^[1] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON - Canada

^[2] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON - Canada

^[3] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Biostat, Toronto, ON - Canada

^[4] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev Ringvej 75, DK-2730 Herlev - Denmark

^[5] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen - Denmark

^[6] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon - England

^[7] Princess Margaret Canc Ctr, Ontario Canc Inst, Toronto, ON - Canada

^[8] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 - USA

^[9] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 - USA

^[10] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA - USA

^[11] Harvard Med Sch, Boston, MA 02115 - USA

^[12] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA - USA

^[13] Int Agcy Res Canc, Lyon - France

^[14] Univ Naples Federico II, Dipartimento Med Clin & Chirurg, Naples - Italy

^[15] Aarhus Univ, Epidemiol Sect, Dept Publ Hlth, Aarhus - Denmark

^[16] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, Athens - Greece

^[17] Hellen Hlth Fdn, Athens - Greece

^[18] WHO Collaborating Ctr Nutr & Hlth, Unit Nutrit Epidemiol & Nutr Publ Hlth, Athens - Greece

^[19] Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London - England

^[20] Russian NN Blokhin Canc Res Ctr, Dept Epidemiol & Prevent, Moscow - Russia

^[21] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 - USA

^[22] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 - USA

^[23] Univ Aberdeen, Sch Med, Inst Appl Hlth Sci, Aberdeen - Scotland

^[24] Vanderbilt Univ, Med Ctr, Dept Thorac Surg, Nashville, TN - USA

^[25] Vanderbilt Univ, Med Ctr, Div Epidemiol, Nashville, TN - USA

^[26] Univ Oviedo, Fac Med, Campus Cristo, Oviedo - Spain

^[27] CIBERESP, Campus Cristo, Oviedo - Spain

^[28] Carmel Hosp, Clalit Natl Canc Control Ctr, Haifa - Israel

^[29] Technion Fac Med, Haifa - Israel

^[30] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 - USA

^[31] Univ N Carolina, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC 27515 - USA

^[32] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 - USA

^[33] Huntsman Canc Inst, Dept Populat Hlth Sci, Salt Lake City, UT - USA

^[34] Univ Bristol, Sch Oral & Dent Sci, Bristol, Avon - England

^[35] Georg August Univ, Univ Med Ctr, Dept Genet Epidemiol, Gottingen - Germany

^[36] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg - Germany

^[37] Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Munich - Germany

^[38] Tech Univ, Inst Med Stat & Epidemiol, Munich - Germany

^[39] German Canc Res Ctr, Div Epigenom & Canc Risk Factors, Heidelberg - Germany

^[40] Univ Liverpool, Inst Translat Med, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool, Merseyside - England

^[41] Univ Sheffield, Sch Hlth & Related Res, Sheffield, S Yorkshire - England

^[42] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen - Netherlands

^[43] Natl Inst Occupat Hlth, Oslo - Norway

^[44] Univ Sao Paulo, Fac Saude Publ, Sao Paulo - Brazil

^[45] Sch Med Sao Jose Do Rio Preto, Dept Mol Biol, Sao Jose Do Rio Preto - Brazil

^[46] Univ Sao Paulo, Fac Med, Hosp Clin, Disciplina Cirurgia Cabeca & Pescoco LIM28, Sao Paulo - Brazil

^[47] Univ Sao Paulo, Sch Dent, Dept Oral Pathol, Sao Paulo - Brazil

^[48] BC Canc Agcy, Vancouver, BC - Canada

^[49] Univ Sao Paulo, Fac Med, Dept Med Prevent, Sao Paulo - Brazil

^[50] Maastricht Univ, Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, Maastricht - Netherlands

^[51] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol, Nijmegen - Netherlands

^[52] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 - USA

^[53] Catalan Inst Oncol ICO IDIBELL, Unit Nutr & Canc, Barcelona - Spain

^[54] Dartmouth Coll, Geisel Sch Med, Dept Epidemiol, Hanover, NH 03755 - USA

^[55] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL - USA

^[56] Lund Univ, Skane Univ Hosp, Lund - Sweden

^[57] Univ Kentucky, Markey Canc Ctr, Lexington, KY - USA

^[58] Washington State Univ, Coll Pharm, Spokane, WA - USA

^[59] Nofer Inst Occupat Med, Dept Environm Epidemiol, Lodz - Poland

^[60] Palacky Univ, Fac Hlth Sci, Olomouc - Czech Republic

^[61] Charles Univ Prague, Fac Med 2, Inst Publ Hlth & Prevent Med, Prague - Czech Republic

^[62] Clin Ctr Serbia, Serv Pathol, Dept Thoracopulm Pathol, Belgrade - Serbia

^[63] Natl Inst Publ Hlth, Bucharest - Romania

^[64] Maria Sklodowska Curie Inst Oncol, Dept Canc Epidemiol & Prevent, Ctr Canc, Warsaw - Poland

^[65] Univ Cattolica Sacro Cuore, Inst Publ Hlth, Sect Hyg, Rome - Italy

^[66] IRCCS, Fdn Policlin Univ A Gemelli, Rome - Italy

^[67] Icahn Sch Med Mt Sinai, New York, NY 10029 - USA

^[68] Baylor Coll Med, Inst Clin & Translat Res, Houston, TX 77030 - USA

• Tipo de documento: Artigo Científico
• Fonte: International Journal of Epidemiology; v. 48, n. 3, p. 751-766, JUN 2019.
• Citações Web of Science: 1

Resumo

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 x 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. (AU)

• Processo FAPESP: 10/51168-0 - Fatores ambientais, clínicos, histopatológicos e moleculares associados ao desenvolvimento e ao prognóstico de carcinomas epidermoides de cabeça e pescoço
• Beneficiário: Eloiza Helena Tajara da Silva
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 01/01768-2 - Estudo internacional de fatores ambientais, vírus e câncer de cavidade oral e de laringe
• Beneficiário: José Eluf Neto
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 04/12054-9 - Busca de marcadores de agressividade em tumores de cabeça e pescoço
• Beneficiário: Eloiza Helena Tajara da Silva
• Linha de fomento: Auxílio à Pesquisa - Temático