Genomic alterations in thymoma—molecular pathogenesis?

Felicitas Oberndorfer, Leonhard Müllauer


Thymomas and thymic carcinomas (TCs) are neoplasms of thymic epithelial cells. Thymomas exhibit a low mutational burden and a few recurrently mutated genes. The most frequent missense mutation p.(Leu404His) affects the general transcription factor IIi (GTF2I) and is specific for thymic epithelial tumors (TETs). The clinically indolent types A and AB thymomas express the miRNA cluster C19MC. This miRNA cluster known to be the largest in the human genome, is—with expression otherwise restricted mostly to embryonal tissue—silenced in the more aggressive type B thymomas and TCs. Thymomas associated with the autoimmune disease myasthenia gravis (MG) exhibit more frequent gene copy number changes and an increased expression of proteins homologous to molecules that are targets for autoantibodies. TCs, however, display a higher mutational burden, with frequent mutations of TP53 and epigenetic regulatory genes and loss of CDKN2A. The knowledge of molecular alterations in TETs fosters the understanding of their pathogenesis and provides guidance for further studies that may lead to the development of targeted therapies.