Insights into Epigenetic Changes Related to Genetic Variants and Cells-of-Origin of Pancreatic Neuroendocrine Tumors: An Algorithm for Practical Workup

SIMPLE SUMMARY: Pancreatic neuroendocrine tumors are composite entities due to their heterogeneity illustrated in clinical behavior, mutational pattern, and site of origin. Pancreatic neuroendocrine tumors display a low mutation burden with frequently epigenetic alterations, such as histone modifications, chromatin remodeling, or DNA methylation status. Using the epigenomic data of the pancreatic neuroendocrine tumors converged to the identification of molecularly distinct subgroups. Furthermore, epigenetic signatures could be used as biomarkers due to their link to cell lineages and genetic driver mutations. We integrated the current knowledge on genetic and epigenetic alterations involved in endocrine lineage associated with these neoplasms to present a pathway-based overview. In this review, we suggest a simplified algorithm on how to manage pancreatic neuroendocrine tumors from a practical perspective based on pathologist ’analysis. ABSTRACT: Current knowledge on the molecular landscape of pancreatic neuroendocrine tumors (PanNETs) has advanced significantly. Still, the cellular origin of PanNETs is uncertain and the associated mechanisms remain largely unknown. DAXX/ATRX and MEN1 are the three most frequently altered genes that drive PanNETs. They are recognized as a link between genetics and epigenetics. Moreover, the acknowledged impact on DNA methylation by somatic mutations in MEN1 is a valid hallmark of epigenetic mechanism. DAXX/ATRX and MEN1 can be studied at the immunohistochemical level as a reliable surrogate for sequencing. DAXX/ATRX mutations promote alternative lengthening of telomeres (ALT) activation, determined by specific fluorescence in situ hybridization (FISH) analysis. ALT phenotype is considered a significant predictor of worse prognosis and a marker of pancreatic origin. Additionally, ARX/PDX1 expression is linked to important epigenomic alterations and can be used as lineage associated immunohistochemical marker. Herein, ARX/PDX1 association with DAXX/ATRX/MEN1 and ALT can be studied through pathological assessment, as these biomarkers may provide important clues to the mechanism underlying disease pathogenesis. In this review, we present an overview of a new approach to tumor stratification based on genetic and epigenetic characteristics as well as cellular origin, with prognostic consequences.