Thymic epithelial neoplasms (TENs), including thymoma and thymic carcinoma, are rare but clinically relevant tumors originating in the anterior mediastinum. Myasthenia gravis (MG), a prototypical antibody-mediated autoimmune neuromuscular disorder, is commonly associated with TENs. Approximately 30-40% of patients with thymoma develop MG, and conversely, thymic tumors are detected in a notable proportion of MG patients. Despite this well-established clinical relationship, the underlying etiological mechanisms-whether immunological, genetic, or structural-remain incompletely understood. Existing research is largely limited to single-center case series or small retrospective studies, lacking population-based validation and genetic integration. To address these gaps, this project will utilize the UK Biobank’s extensive genotypic and phenotypic data to explore the epidemiological, genetic, and clinical interplay between TENs and MG in a large prospective cohort. We aim (1) to define the prevalence, co-occurrence, and temporal sequence of these two conditions using ICD-coded diagnoses and cancer registry data; (2) to identify shared genetic risk factors and immunogenetic signatures through polygenic risk scores and Mendelian randomization analyses; and (3) to evaluate the clinical implications of comorbidity, including prognosis and treatment response, using Cox models and predictive modeling. This research builds on immunological theories suggesting that disrupted thymic architecture may lead to systemic autoimmunity, yet aims to test such hypotheses at the population level with rigorous statistical methodology. The integrative approach-combining genomic, clinical, and epidemiological data with advanced modeling techniques-has the potential to uncover novel mechanisms underlying tumor-associated autoimmunity and inform precision strategies for diagnosis, surveillance, and care in patients with TENs, MG, or both.
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