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

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 Pa...

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Bibliographic Details
Published in:Cancers 2022-09, Vol.14 (18), p.4444
Main Authors: Ciobanu, Oana A., Martin, Sorina C., Herlea, Vlad, Fica, Simona
Format: Article
Language:English
Subjects:
Algorithms
Biomarkers
Cancer
Causes of
Chromatin remodeling
Daxx protein
DNA methylation
Epigenetic inheritance
Epigenetics
Fluorescence in situ hybridization
Gene expression
Genetic aspects
Genetic diversity
Genetic variation
Health aspects
Histones
Hormones
Influence
Mutation
Neuroendocrine tumors
Pancreas
Pancreatic tumors
Phenotypes
Proteins
Review
Telomeres
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14184444