Patients with thymic epithelial tumors (TETs) frequently show coexistence of various paraneoplastic syndromes, which severely affect their survival. Moreover, there is a lack of effective clinical treatment strategies for patients with unresectable metastatic and recurrent TETs.

To explore the genetic alterations that play a key role in the pathogenesis of TETs, we analyzed the whole-exome sequencing data from 24 patients diagnosed to have TETs at the First Affiliated Hospital of Nanjing Medical University.

Mutated genes in TETs were enriched in several hormone-associated pathways such as insulin secretion; Cushing syndrome; parathyroid hormone; and thyroid hormone, as well as multiple classical tumor-associated pathways, including cAMP, Notch, PI3K-Akt, and WNT signaling pathway. Patients with paraneoplastic syndromes (PNS) exhibited more pronounced alterations in hormone-related pathways. RHPN2 is the most frequently mutated gene in TETs. TETs with RHPN2 mutation showed greater upregulation of the hormone-related signaling pathways such as thyroid hormone and parathyroid hormone as well as a trend toward shorter survival of patients.

We analyzed the possible role of hormones in TETs on several levels, explored potential links between hormones and other genetic mutations, and found that RHPN2 may be a potentially valuable gene.