Evaluating Genetic Alterations in Metastatic Pancreatic Neuroendocrine Tumors with Potential Therapeutic and Prognostic Applications: A Comparative In Silico Study with Metastatic Neuroendocrine Tumors Originating from the Small Intestine and Rectum

Abstract Introduction/Objective Pancreatic neuroendocrine tumors (P-NET) are diverse tumors with slow growth and varying levels of potential malignant behavior. The overall 5-year survival rates for P-NET are approximately 95%, 72%, and 23% if localized, and in cases of regional and distant metastasis respectively. These tumors exhibit a low rate of mutations but show varied genomic abnormalities, contributing to their unpredictable nature. In this study, we aimed to find the genetic alterations observed in metastatic P-NET for their potential therapeutic and prognostic applications and compared these tumors to metastatic neuroendocrine tumors originating from the small intestine (SI-NET) and rectum (R-NET). Methods/Case Report We initially extracted RNA-seq datasets from the GEO database. Next, we analyzed the datasets in six defined groups and differentially expressed genes were obtained by comparison to controls. Either of the groups of P-NET, SI-NET, or R-NET cases were evaluated individually and altogether (primary vs metastatic; 4 groups) and in 2 groups comparing primary/metastatic P-NET cases to primary/metastatic cases of SI-NET plus R- NET. Using a Venn diagram, we isolated the commonality between gene expression profiles. Afterward, we obtained the ontology of genes and signaling pathways from KEGG and Enrichr. Finally, we drew the protein network and evaluated the proteins in GEPIA and TCGA clinical databases. Results (if a Case Study enter NA) A total of 212 cases including 113 P-NET (83 primary and 30 metastatic), 81 SI- NET (44 primary and 37 metastatic), and 18 R-NET (3 primary and 15 metastatic) were selected. We found 8 genes (ORM1, HP, APOA2, HRG, KNG1, ALB, SERPINC1, and AHSG) are mutually markedly upregulated in cases of metastatic P-NET and SI-NET but were not identified in metastatic R-NET. The products of these genes were predominantly involved in complement cascades. CABYR, MYCN, and CALU genes were among the most upregulated genes specifically isolated in the metastatic P-NET that played roles in activating intracellular signaling pathways, transcription, and protein folding. Conclusion The shared upregulated genes in metastatic P-NET and SI-NET may support the relatively better prognosis of these tumors in comparison to the metastatic R-NET due to the activation of the complement cascade (immune system). Furthermore, the identified genetic alterations in the metastatic P-NET cases may have potential therapeutic and prognostic applications for future use.