Comparative transcriptomics of functional vs non-functional pituitary neuroendocrine tumors

NP. Pace*^a (Dr), N. Mercieca^a (Mr), R. Formosa^a (Dr), EJ. Spiteri^a (Ms), O. Mazzitelli^a (Dr), M. Gruppetta^a (Dr), JP. Ebejer^a (Dr), D. Saliba^a (Prof), J. Vassallo^a (Prof)

^a University of Malta, Msida, MALTA

* nikolai.p.pace@um.edu.mt

Introduction

Pituitary neuroendocrine tumors are a heterogeneous group of neoplasms derived from the adenohypophysis. Their pathogenesis is poorly understood, and they exhibit extensive clinical and molecular heterogeneity that precludes the development of targeted therapeutic modalities. Despite the benign histological features of most pituitary neuroendocrine tumors, they produce clinical manifestations due to a combination of compressive effects and/or hormonal hypersecretion by functional tumors. Their gene expression profile is highly heterogeneous, with a lack of a uniform molecular signature across tumor subtypes. While several genes have been consistently implicated across various transcriptomic studies, individual studies also identify novel DEGs with potential tumorigenic and therapeutic implications. The objective of this study was to further explore transcriptomic changes between functional vs non-functional pituitary neuroendocrine tumors, and to relate gene expression changes to deregulated biological pathways.

Materials and Methods

Whole transcriptome analysis was performed on RNA extracted from 27 non-functioning pituitary adenomas (NFPAs) and 21 functional adenomas (FPAs) using the BGI-Seq500 platform. Following quality control and pre-processing, sequencing reads were mapped to hg19. The limma package was used to evaluate differentially expressed genes (DEGs), and gene set enrichment analysis (GSEA) using KEGG and Reactome datasets was performed.

Results

1817 DEGs with a log2 fold change of more than ±2 were identified in the NFPA-FPA comparison, with 1200 upregulated and 617 downregulated genes in NFPAs. K-means clustering identified two gene clusters with opposing patterns of expression between NFPA and FPA, with upregulation cation transmembrane transporter activity signaling in NFPAs and upregulation of GH signaling and retinoic acid signaling in FPAs. GSEA analysis revealed downregulation of JAK-STAT and PI3K-Akt/mTOR signaling and upregulation of oxidative phosphorylation and calcium signaling pathways in NFPAs. The top up-regulated NFPA genes include BRINP3, GALNT12, SERPINF1, GATA3 and FOLR1. GATA3 is paralogous to GATA2 which is required for the differentiation of gonadotrophs and thyrotropes. NFPAs exhibit upregulation of ion-related events, while FPAs demonstrate upregulation of GH and tumorigenesis-related pathways driven by STAT3, a key regulator of GH expression.

Conclusion

This analysis expands the molecular profile of functional vs non-functional pituitary tumors and presents potential novel targets for further analysis.

The author has declared no conflict of interest.