ESPE Abstracts

The present study aimed to determine the mutational and molecular landscape of a 17 mm insulinoma from a fifteen-year-old male. Using targeted exome sequencing and microarray, we investigated somatic candidates in the insulinoma. The microarray analysis was conducted using 12 other insulinomas as a control group and revealed a total of 1907 differentially expressed genes (P-value < 0.05, FDR P-value < 0.05). After thorough gene variant filtering, we identified two putative candidate genes: OGDH and FGFR1. Both variations were detected as missense variants, located in highly conserved regions, and predicted to be damaging by five different prediction tools. OGDH encodes a pivotal subunit of the 2-oxoglutarate dehydrogenase complex, which is an enzyme in the citric acid cycle catalyzing the conversion of 2-oxoglutarate (α-ketoglutarate) to succinyl-CoA and CO2. Interestingly, the enzyme also has a nuclear function in complex with KAT2A, where the enzyme activity is crucial for the succinylation of H3K79, and dysregulation is observed in several cancer types. We identified a missense variant (variant allele frequency: 0.10) located in the active site of the enzyme (Ser458Pro). The alteration diminishes two hydrogen bonds, thus probably affecting the stability of the protein structure. The potentially compromised structure affects the enzyme reaction, leading to an accumulation of the substrate α-ketoglutarate. This may induce the reductive citric acid cycle, which stimulates insulin secretion via NADPH-mediated insulin exocytosis. The second candidate gene FGFR1 encodes the fibroblast growth factor receptor 1, responsible for e.g. survival and proliferation. The insulinoma contained a variant (Glu692Lys, variant allele frequency: 0.11) in the tyrosine kinase domain and identical variants have been detected earlier in analogous residues in the growth factor receptors FGFR4 (residue Glu681Lys) and ERBB2 (residue Glu914Lys) in lung adenocarcinoma and glioblastoma, respectively. Additionally, our microarray analysis indicated that the gene expression of FGFR1 was increased by 3.85 fold (P-value: 0.0023, FDR P-value: 0.0305). A direct association between FGFR1 activity and the pancreatic transcription factor PDX1 has been proposed, and the latter plays a crucial role in the establishment, functionality and maturity of beta cells. The activation of FGFR1 induces the gene expression of PDX1, which works as a transcriptional activator of insulin and somatostatin amongst others. Consistently, the gene expression of SST, which encodes somatostatin, was increased 1494 fold compared to the other 12 insulinomas analyzed using microarray. These findings reveal two new insulinoma candidate genes with functional roles associated with regulation of insulin secretion.