Type B3 Thymoma With a Novel KMT2A::MAML3 Fusion: Expanding the Spectrum of Gene Fusions Beyond the MAML2 Gene

Abstract

Mastermind-like transcriptional coactivator (MAML) gene fusions have been documented in Thymic Epithelial Tumors (TETs). Specifically, lysine methyltransferase 2A (KMT2A)::MAML2 gene fusions are associated with type B2 and B3 thymomas. Here, we report for the first time a young patient with invasive type B3 thymoma harboring a novel KMT2A::MAML3 gene fusion. MAML3 and MAML2 are paralogues. In addition to the classic type B3 thymoma histology, this article documents intratumor heterogeneity, characterized by a trabecular and fascicular pattern, as well as areas of clear cells. Immunohistochemistry showed keratin positivity in tumor cells, while neuroendocrine markers were negative in trabecular regions. DNA-based next-generation sequencing failed to identify pathogenic variants, but RNA sequencing detected the KMT2A::MAML3 gene fusion. We compared the gene fusion sites of MAML2 and MAML3, focusing on exon 2, and found that they share similar functional protein domains. Moreover, the same domain appeared downstream of the KMT2A::MAML2 fusion protein. Therefore, we hypothesize that MAML3 gene fusions, like MAML2, lead to abnormal Notch signaling pathways and increase the invasive potential of certain thymoma subtypes. Our findings expand the genetic landscape of aggressive thymomas and offer new insights for molecular studies in TETs.