Long Leukocyte Telomere Length Is Associated with Increased Risks of Soft Tissue Sarcoma: A Mendelian Randomization Study

Background: Leukocyte telomere length (LTL) has been associated with the risks of several cancers in observational studies. Mendelian randomization (MR) studies, using genetic variants as instrumental variables, have also shown associations of genetically predicted LTL with cancer risks. In this study, we performed the first MR analysis on soft tissue sarcoma (STS) to investigate the causal relationship between LTL and the risk of STS. Methods: Genotypes from eleven LTL-associated single nucleotide polymorphisms (SNPs) in 821 STS cases and 851 cancer-free controls were aggregated into a weighted genetic risk score (GRS) to predict LTL. Multivariate logistic regression was used to assess the association of STS risk with individual SNPs and aggregated GRS. Results: Four SNPs displayed evidence for an individual association between long LTL-conferring allele and increased STS risk: rs7675998 (odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.02–1.43), rs9420907 (OR = 1.31, 95% CI = 1.08–1.59), rs8105767 (OR = 1.18, 95% CI = 1.02–1.37), and rs412658 (OR = 1.18, 95% CI = 1.02–1.36). Moreover, longer genetically predicted LTL, calculated as GRS, was strongly associated with an increased risk of STS (OR = 1.44, 95% CI = 1.18–1.75, p < 0.001), and there was a significant dose-response association (p for trend <0.001 in tertile and quartile analyses). The association of longer LTL with higher STS risk was more evident in women than in men. In stratified analyses by major STS subtypes, longer LTL was significantly associated with higher risks of leiomyosarcoma and gastrointestinal stromal tumors. Conclusions: Longer LTL is associated with increased risks of STS.