Autoimmune thyroiditis and pan-cancer risk: A comprehensive Mendelian randomization study

Introduction: Autoimmune thyroiditis (AIT), clinically termed Hashimoto’s thyroiditis (HT), is a chronic autoimmune condition characterized by progressive immune-mediated degeneration of thyroid tissue. The association between AIT and cancer risk, particularly thyroid cancer, remains controversial. Objective: This study is aimed to investigate potential causal associations between AIT/HT and thyroid cancers or extra-thyroidal cancers comprehensively. Methods: To clarify this uncertainty, we employed Mendelian randomization (MR) analysis to evaluate causal associations between genetic predisposition to AIT and pan-cancer risk, including subtypes of thyroid cancer and extra-thyroidal malignancies. Summary statistics were pooled from comprehensive genome-wide studies, including two independent AIT/HT datasets, 10 thyroid neoplasm datasets, and 33 extra-thyroidal cancer datasets. Bidirectional two-sample MR analyses were conducted to mitigate confounding and reverse causation. Quality control was reinforced through sensitivity analyses. Results: Contrary to previous observational studies, our study found no genetically supported causal link between AIT/HT and the development of thyroid carcinoma. However, elevated risks of non-Hodgkin lymphoma, primary lymphoid/hematopoietic malignancies, testicular cancer, and brain cancer might be associated with AIT/HT. Sensitivity analyses confirmed the robustness of these results, although some associations exhibited heterogeneity or pleiotropy. Conclusion: These findings reveal tissue-specific effects of thyroid autoimmunity on cancer development, suggesting distinct biological pathways beyond thyroid malignancies. This study provides genetic evidence that refines cancer risk assessment in patients with AIT/HT and emphasizes the need for further mechanistic research to elucidate underlying biological processes.