Understanding the impact of <i>GTF2I</i> mutations in thymic epithelial tumors: Characteristics and clinicogenomic outcomes.

Abstract

e20173 Background: Thymic epithelial tumors (TETs) are rare malignancies that include thymomas, thymic carcinomas, and thymic neuroendocrine tumors. The GTF2I mutation has been reported frequently in indolent subtypes and is associated with better prognosis, but key aspects of the mutation remain poorly defined. Its incidence across thymic tumor subtypes in large, integrated datasets has not been fully characterized. Clinicogenomic associations, including co-mutational patterns and relationships with tumor mutational burden (TMB), have also not been elucidated. We used publicly accessible cohorts to evaluate the prevalence of GTF2I mutations and to clarify its potential role in molecular classification and clinical management. Methods: We queried publicly accessible TET cohorts within cBioPortal to identify tumors harboring GTF2I mutations. We created a cohort of 403 patients collected from 4 studies. The clinicogenomic data was analyzed to quantify the expression of GTF2I and describe the characteristics of these patients. Results: Of the 403 patients, 178 (44.2%) patients had the GTF2I mutation. Among those the GTF2I mutation, 46.6% of those with mutation were female compared to 35.9% of those without (p = 0.633). The ethnic distribution was similar in mutated and non-mutated groups (p = 0.920). The mean age at diagnosis was higher in the GTF2I positive cohort (61.65 ± 11.23 vs 55.03 ± 13.58 years, p &lt; 0.01). Co-expression data revealed that GTF2I positive TET had higher rates of HRAS (16.85 vs 0.45%, p &lt; 0.01) and TRGJP (16.29 vs 9.42%, p &lt; 0.01) gene alteration event frequencies. TMB of GTF2I mutated cohort was lower than that without the mutation (0.5 ± 0.28 vs 0.68 ± 2.36 mut/Mb, p &lt; 0.01). Of note, patients without the mutation had higher rates of receiving radiation therapy (18.3% vs 50.0%, p &lt; 0.01). Patients in the unaltered group had significantly worse overall survival than those in the altered group (HR 2.56, 95% CI 1.19–5.49; log-rank p = 0.0345). Conclusions: Nearly half of TET patients carried the GTF2I mutation, with a higher incidence in indolent histologies (95% in Type A and 85% in Type AB vs 10% in Type C), suggesting its potential as a molecular adjunct to histologic diagnosis. This would be particularly helpful in settings where morphologic interpretation is challenging, or tumor heterogeneity obscures accurate classification. Additionally, given the typically indolent nature of mutation-positive TET, GTF2I mutation status may inform treatment de-intensification, as survival trajectories in mutation-negative TETs may evolve substantially with expanding immunotherapy use, particularly given its association with high TMB. Distribution of altered and unaltered samples across thymoma subtypes. Disease Type Altered (%) Unaltered (%) Thymoma- Type A 95 5 Thymoma- Type AB 85 15 Thymoma- Type B1 20 80 Thymoma- Type B2 27 73 Thymoma- Type B3 25 75 Thymoma- Type C 10 90