Transcriptomic analysis of PanNET tumor progression from microtumor to metastasis in MEN1 patients (A05)

Introduction: Pancreatic Neuroendocrine Neoplasms (PanNENs) are a major component the Multiple Endocrine Neoplasia 1 Syndrome (MEN1). Although multiple pancreatic neuroendocrine microtumors (microadenomatosis) are a histomorphological hallmark of MEN1, their molecular status compared to PanNET as well as their metastasis remains unclear.

Aim(s): In this study we aim to understand the mechanisms underlying PanNET progression in MEN1 patients by comparing transcription profiles of pancreatic microtumors to tumor and their metastases of the same patient.

Materials and methods: Five MEN1 patients with resected pancreatic lesions in different stages (normal islets, microtumors, PanNET and metastases) were included. Individual lesions have been dissected using laser microdissection from PAXgene fixed material. RNAseq analysis of pooled normal pancreatic islets, 8 microadenomas, 4 PanNET and 1 PanNET metastasis was performed.

Results: Our analysis showed significant differential gene expression throughout all stages. While Microadenomas turned-out to be very similar to normal islets, they already exhibit a downregulation of pathways involved in hormone synthesis and upregulating pathways responsible for migratory activity and angiogenesis. At the stage of PanNET, further downregulation of the hormonal synthesis is observed while additional upregulation of the pathways involved in the epithelial mesenchymal transition and response to hypoxia is observed.

Conclusion: Our work unveiled significant transcriptional differences between the progression stages of PanNETs. Further exploration of these signatures will not only clarify disease pathogenesis in MEN1 patients, but also identify potential therapeutic targets associated with MEN1 mutations.

Keywords: microtumor, men1, pannets, rnaseq, transcriptomics, progression