The causal relationship between telomere length and cancer risk: A two-sample Mendelian randomization.

Abstract

Background: Telomere length shortens with age and is associated with an increased risk of numerous chronic diseases. However, the causal direction between telomere length and cancer risk remains uncertain. This study aimed to assess the causal impact of telomere length on cancer risk using Mendelian randomization(MR) analysis.

Methods: Genome-wide association studies(GWAS) from Singapore and China data, the Korean Cancer Prevention Study(KCPS)-II, the Korean Genome Epidemiologic Study(KoGES), and the Biobank of Japan(BBJ) were utilized. A two-sample MR study was performed using summary-level GWAS data from individuals of East Asian ancestry. Single nucleotide polymorphism(SNPs) associated with telomere length were used as instrumental variables.

Results: Longer telomere length per 1SD increase due to germline genetic variants was associated with a higher risk of site-specific cancer. In the KCPS-II and KOGES, the strongest association was observed with thyroid cancer[OR 2.49(95%CI, 1.79-3.47), 2.27(1.49-3.46)], followed by lung cancer [OR 2.19(95%CI, 1.60-3.08) and 1.45(1.12-1.87)]. Similar results were observed in BBJ, with OR 2.92(95%CI, 1.75-4.88) for thyroid cancer and 2.04(1.41-2.94) for lung cancer. In histological subgroup analysis of KCPS-II, a significant relationship was found with lung adenocarcinoma [(OR 2.26(95%CI, 1.55-3.31)] but not with lung squamous cell carcinoma(1.21, 0.47-3.06). After removing outlier SNPs in the radial MR analysis, significant associations were identified for both lung adenocarcinoma [(OR 1.88(95%CI, 1.25-2.82)] and lung squamous cell carcinoma (2.29,1.05-4.98).

Conclusion: Our findings suggest that longer telomere length increases the risk of various cancers in East Asian populations.

Impact: Genetically determined longer telomere length may contribute to a risk of certain cancers.