Non-Mutational Key Features in the Biology of Thymomas

Simple Summary Organotypic features such as intratumoral thymopoiesis make thymomas (THs) unique tumors. Their remarkable histological heterogeneity and low mutational burden have largely precluded personalized therapies. Although most thymomas do not harbor known oncogenic driver mutations, common non-mutational key features such as chromosomal, epigenetic, and metabolic alterations are emerging that converge into a limited number of critical cellular pathways that may provide opportunities for therapeutic interventions. In this review, we have attempted to integrate the existing knowledge of TH biology into a broader picture and highlight opportunities for targeted treatment options in these non-mutated tumors.Abstract Thymomas (THs) are a unique group of heterogeneous tumors of the thymic epithelium. In particular, the subtypes B2 and B3 tend to be aggressive and metastatic. Radical tumor resection remains the only curative option for localized tumors, while more advanced THs require multimodal treatment. Deep sequencing analyses have failed to identify known oncogenic driver mutations in TH, with the notable exception of the GTF2I mutation, which occurs predominantly in type A and AB THs. However, there are multiple alternative non-mutational mechanisms (e.g., perturbed thymic developmental programs, metabolism, non-coding RNA networks) that control cellular behavior and tumorigenesis through the deregulation of critical molecular pathways. Here, we attempted to show how the results of studies investigating such alternative mechanisms could be integrated into a current model of TH biology. This model could be used to focus ongoing research and therapeutic strategies.