Abstract 6487: Association between telomere length and overall survival in lung cancer patients: a mendelian randomization study
Authors: Zhai Ting , Christiani David C. , Nagel Zachary D. 
Published: April 2023

Abstract
Background: An association between chronological age and poor lung cancer survival is well established, but it is unclear whether accelerated biological aging may also predispose lung cancer patients to worse survival outcomes. While telomere shortening in blood cells is a biomarker of aging, its relationship to lung cancer prognosis remains unclear due to limited sample size, confounding, and reverse causation from observational studies. As telomere length could be a precursor of worse prognosis, a causal inference method is needed to clarify the role of telomere length in predicting lung cancer outcomes.
Methods: A Mendelian Randomization study for the causal relationship between telomere length and overall survival in lung cancer was carried out. We searched the GWAS catalog for single-nucleotide polymorphisms (SNPs) associated with telomere length and collected effect estimates for the association between each SNP and telomere length from the literature. The summary data for all SNPs were acquired by analyzing their associations with overall survival of lung cancer patients in the Boston Lung Cancer Study (BLCS) and through Cox proportional hazards regression. The effect size of telomere length on overall survival was calculated and compared through several weighting methods including inverse-variance weighting (IVW) and MR-Egger.
Results: A total of 16 SNPs were identified as the genetic instruments for telomere length. 1798 lung cancer patients from BLCS provided survival data with a median follow-up of 33 months. Surprisingly, a non-significant positive trend was observed for the association between telomere length and overall survival across the weighting methods (IVW: HR 1.718, 95%CI 0.849 - 3.476; MR-Egger: HR 2.347, 95%CI 0.592 - 9.309). Further analysis is ongoing to incorporate more patients and genetic instruments for additional markers of biological aging in the BLCS to explore the source of heterogeneity (I2= 98.1%) in the present study and gain more power for detecting the underlying relationship between telomere length and overall survival in lung cancer.
Conclusion: A positive trend between telomere length and risk of death in lung cancer patients is consistent with previous reports of an association between increased cancer risk and longer telomere length, but is seemingly at odds with an established link between chronological age and poor lung cancer prognosis. Since markers of biological aging are strongly correlated with chronological age, we conclude that a more robust assessment of biological age will be needed to clarify the causal relationship between telomere length and lung cancer prognosis.
Citation Format: Ting Zhai, David C. Christiani, Zachary D. Nagel. Association between telomere length and overall survival in lung cancer patients: a mendelian randomization study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6487.