Causal association between telomere length and female cancers: a two-sample Mendelian randomization study.

Purpose: To explore the causal associations between genetically predicted telomere length and gynecologic and breast cancers.

Methods: This Mendelian randomization study used data from genome-wide association studies on telomere length and breast (BC), cervical cancer, endometrial (EC), and ovarian (OC) cancers. The primary analysis was performed using the inverse variance weighted (IVW) method, with confirmation using the weighted median, weighted mode, and MR-Egger methods. Heterogeneity was detected using Cochran's Q-test, horizontal pleiotropy using MR-Egger regression, outliers using MR-PRESSO, and discordant single-nucleotide polymorphisms using the leave-one-out method.

Results: The genetic prediction results indicated causal associations between the risk of telomere length and EC [IVW; OR = 1.29, 95% confidence interval (95%CI): 1.05-1.59, P = .02], leukocyte telomere length and EC (IVW; OR = 1.23, 95%CI: 1.01-1.51, P = .04), telomere length and OC (IVW; OR = 1.27, 95%CI: 1.01-1.60, P = .04), telomere length and BC (IVW; OR = 1.12, 95%CI: 1.01-1.23, P = .03), and leukocyte telomere length and BC (IVW; OR = 1.12, 95%CI: 1.02-1.24, P = .02). Cochran's Q-test revealed heterogeneity for telomere length and BC (P < .001), leukocyte telomere length and BC (P < .001), and B-cell telomere length and BC (P = .012). The MR-Egger regression results suggest that the analyses of telomere length and BC (P = .014) and leukocyte telomere length and BC (P = .044) were influenced by horizontal pleiotropy. The MR-PRESSO analysis indicated the presence of outliers in the analyses of telomere length and BC and leukocyte telomere length and breast cancer. After removing the outliers, the statistical significance remained.

Conclusion: This MR study suggests a causal association between telomere length and BC, EC, and OC, warranting additional study. Key message What is already known on this topic?  Previous research has indicated an association between telomere length and the risk of various cancers, including breast and gynecologic cancers. However, the causal relationship remained unclear, necessitating further exploration to establish whether telomere length could be a modifiable risk factor for these cancers. What this study adds?  This study provides robust evidence of a causal relationship between genetically predicted telomere length and an increased risk of breast cancer, endometrial cancer, and ovarian cancer, with specific odds ratios indicating a significant association. It highlights that both leukocyte and overall telomere length are important factors in cancer risk. How this study might affect research, practice, or policy?  The findings could inform future research into telomere length as a biomarker for cancer risk, promote investigations into telomere-targeting interventions, and influence guidelines on screening and preventive strategies for at-risk populations based on genetic predispositions.