Scientific Program

Abstract:

Functional pancreatic neuroendocrine tumors (PNETs) may be hereditary or sporadic. Hereditary forms are often caused by MEN1 mutations. The majority of insulinomas are sporadic, solitary and low-grade. The tumorigenesis in sporadic insulinomas is not well described. We describe the secondary events following the first hit MEN1 variant and the mutational profile of both MEN1 insulinomas and sporadic tumors. We included tissue from 4 MEN1 patients and 12 patients with sporadic PNETs for NGS exom analysis, transcriptomic analysis, histology and immunohistochemistry.
Variant call on all samples was performed using the GATK pipeline and variant filtering in Varseq software. CNV and LOH analysis was performed using Varseq based on Z-score, ratio-plot, and VAFs metrics. RNA was extracted from all tissue and processed for hybridization to Clariom S arrays using GeneChip Hybridization. Analysis was performed using the Transcriptome Analysis Console (TAC) software in combination with the R script for further analysis. IHC stainings against insulin, glucagon, synaptophysin, islet-1 and Ki67 were conducted for all insulinoma. specimens. This is the first study to evaluate the occurrence of a second hit in the MEN1 gene in PNENs from young patients with MEN1 syndrome on DNA, RNA and protein level.
Our study of sporadic insulinomas revealed a marked genetic heterogeneity with few recurrent alterations among candidate genes. Our findings give novel insights into beta-cell pathophysiology and insulin secretion, which provide the framework for future studies on possible drug targets in diabetes and hyperinsulinism. Our results will be compared to a metaanalysis of published whole exom and genom sequencing data of well differentiated MEN1 and sporadic PNETs.

Audience Take Away Notes:

• Update on the current knowledge about molecular mechanisms of insulinomas
• Essential knowledge on the route to new drug targets
• We provide a meta-analysis with an update including our recent results of sporadic and MEN1 PNETs pawing the way for new downstream studies

Biography:

Dr. Brusgaard studied molecular biology at Southern Danish University, Institute of Natural sciences and graduated in 1990. Between 1990 and 1993 he was working as an associate professor at Institute of Medical Microbiology, Southern Danish University. He received his PhD degree in 1999 from Aarhus University at the Institute of Human Genetics. After which he was working first as a research fellow and since 2014 as an associate professor at Department of Clinical Genetics, Odense, Denmark. He has published more than 116 research articles in SCI (E) journals.