Causal Association between Genetically Predicted Telomere Length and Breast Cancer Risk: A Bidirectional Two-sample Mendelian Randomization Study

Introduction: Previous studies reported the relationship between telomere length (TL) and breast cancer risk, but the effect of TL on breast cancer risk, especially subtype-specific breast cancer, is still controversial. We used a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal association between TL and breast cancer risk with pre-set individual subtype stratification. Methods: Genetic instruments for TL were obtained from genome-wide association studies (GWAS) of the UK Biobank, which included 472,174 individuals of European ancestry. Breast cancer GWAS summary statistics were obtained from Breast Cancer Association Consortium (BCAC), including 122,977 cases and 105,974 controls for overall and subtype analyses. Inverse-- variance weighted (IVW) is the main method used to estimate odds ratios (ORs) and 95% confidence intervals (CI), and alternative MR methods, including MR-Egger, weighted median, and weighted mode, are estimated. Results: Our study indicated that genetically shorter telomere length (TL) was associated with an increased risk of triple-negative breast cancer (TNBC) (IVW: OR=0.77, 95% CI=0.61-0.96, P =0.02). And a similar causal relationship was also found in BRCA1-mutated TNBC (IVW: OR=0.76, 95% CI=0.64-0.91, P =2.8E-03). Moreover, we did not find any causal effect of TNBC or BRCA1-mutated TNBC on TL, nor did any other breast cancer subtypes have an effect on TL. Discussion: These bidirectional Mendelian randomization analyses support a subtype-specific inverse causal association between genetically determined TL and the risk of TNBC, particularly in BRCA1-mutated TNBC. These findings provide MR-based population-level etiological evidence, highlighting a potential role of telomere biology in specific breast cancer subtypes and warranting further investigation into the underlying biological mechanism. Conclusion: These results highlight the potential importance of telomere biology in TNBC etiology and warrant further investigation into the underlying biological mechanisms.