Abstract 817: Mendelian randomization and mediation analysis of 5p15.33, telomere length and lung cancer risk

Background: Telomere length (TL) is a predictor of lung cancer risk, but the direction of this association differs between and prospective and case-control studies. This discrepancy may be attributed to reverse causation in the latter, due to disease-related changes in TL that is measured after diagnosis or treatment. To overcome these limitations and characterize the relationship between TL and lung cancer risk we carried out observational and mediation analyses, and a 2-stage Mendelian Randomization (MR) analysis, where we developed novel genetic instruments for TL and tested the association with lung cancer using 20 OncoArray studies in the Transdisciplinary Research in Cancer of the Lung group of the International Lung Cancer Consortium. Methods: The observational analysis examined TL measured using qPCR in 1128 cases and 928 controls. Odds ratios (OR) for TL were adjusted for age, sex and cigarette pack-years. Mediation analysis was used to estimate the% of the lung cancer association in 5p15 that operates through TL. To develop novel TL instruments, variants identified through deep sequencing of the 5p15 locus were genotyped in 900 controls. Variants that met MR criteria were combined into a single instrumental variable (IV), and its association with TL was estimated. We also used 6 previously identified TL predictors (p Results: The observational analysis suggested that longer TL is associated with decreased lung cancer risk (OR = 0.94, p = 0.04). This was more pronounced for squamous carcinoma (OR = 0.77, p = 1.1×10-4). We also showed that TL mediates up to 8% (p Conclusions: We developed novel genetic instruments for TL, and confirmed that genetically predicted longer TL is associated with increased lung cancer risk. These findings suggest that previously reported associations of long TL with decreased risk were likely due to residual confounding by smoking, age and/or reverse causation. Citation Format: Linda Kachuri, George Davey Smith, Geoffrey Liu, Maria Teresa Landi, David C. Christiani, Neil E. Caporaso, James D. McKay, Xifeng Wu, Melinda C. Aldrich, Gad Rennert, Dawn Teare, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, John K. Field, Lambertus A. Kiemeney, Adonina Tardon, Aage Haugen, Stephen Lam, Loic Le Marchand, Matthew B. Schabath, Angeline S. Andrew, Mattias Johansson, Jonas Manjer, Philip Lazarus, Susanne Arnold, Gordon Fehringer, Xuchen Zong, Paul Brennan, Stig E. Bojesen, Christopher I. Amos, Rayjean J. Hung. Mendelian randomization and mediation analysis of 5p15.33, telomere length and lung cancer risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 817.