Περίληψη:
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. © 2018 The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
Συγγραφείς:
Kachuri, L.
Saarela, O.
Bojesen, S.E.
Davey Smith, G.
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.
Macfarlane, G.J.
Aldrich, M.C.
Tardón, A.
Rennert, G.
Olshan, A.F.
Weissler, M.C.
Chen, C.
Goodman, G.E.
Doherty, J.A.
Ness, A.R.
Bickeböller, H.
Wichmann, H.-E.
Risch, A.
Field, J.K.
Teare, M.D.
Kiemeney, L.A.
Van Der Heijden, E.H.F.M.
Carroll, J.C.
Haugen, A.
Zienolddiny, S.
Skaug, V.
Wünsch-Filho, V.
Tajara, E.H.
Ayoub Moysés, R.
Daumas Nunes, F.
Lam, S.
Eluf-Neto, J.
Lacko, M.
Peters, W.H.M.
Le Marchand, L.
Duell, E.J.
Andrew, A.S.
Franceschi, S.
Schabath, M.B.
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, J.D.
Brennan, P.
Amos, C.I.
Hung, R.J.
Λέξεις-κλειδιά:
cancer; chromosome; confidence interval; gene expression; genetic analysis; immune system; physiological response, adult; aged; Article; cancer risk; chromosome 5p; controlled study; female; gene locus; genetic susceptibility; genotype; head and neck cancer; human; leukocyte; lung adenocarcinoma; lung cancer; major clinical study; male; Mendelian randomization analysis; middle aged; mouth cancer; oropharynx cancer; people by smoking status; priority journal; squamous cell lung carcinoma; telomere length; chromosome 5; genetics; head and neck tumor; lung adenocarcinoma; lung tumor; Mendelian randomization analysis; metabolism; squamous cell carcinoma; telomere; telomere homeostasis; very elderly, Adenocarcinoma of Lung; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Chromosomes, Human, Pair 5; Female; Head and Neck Neoplasms; Humans; Leukocytes; Lung Neoplasms; Male; Mendelian Randomization Analysis; Middle Aged; Squamous Cell Carcinoma of Head and Neck; Telomere; Telomere Homeostasis
