Epigenetic Regulation in Gastroenteropancreatic Neuroendocrine Tumors

Crabtree, Judy S.

doi:10.3389/fonc.2022.901435

Cited by 7 publications

(5 citation statements)

References 136 publications

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“…Many researchers are addressing this task, with newer studies evaluating prognostic markers that impact treatment outcomes. Multiple parallel avenues of research are focused on better characterizing epigenetic changes in neuroendocrine tumors that may serve as more useful biomarkers, including DNA methylation, histone modification, chromosome shattering, and the tumor microenvironment [ 158 , 159 , 160 , 161 ]. This research has the potential to further elucidate the factors that drive NET progression and to better assess and treat patients living with the disease.…”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine Tumors: Genomics and Molecular Biomarkers with a Focus on Metastatic Disease

Alexander

Ziv

2023

Cancers

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Neuroendocrine tumors (NETs) are considered rare tumors that originate from specialized endocrine cells. Patients often present with metastatic disease at the time of diagnosis, which negatively impacts their quality of life and overall survival. An understanding of the genetic mutations that drive these tumors and the biomarkers used to detect new NET cases is important to identify patients at an earlier disease stage. Elevations in CgA, synaptophysin, and 5-HIAA are most commonly used to identify NETs and assess prognosis; however, new advances in whole genome sequencing and multigenomic blood assays have allowed for a greater understanding of the drivers of NETs and more sensitive and specific tests to diagnose tumors and assess disease response. Treating NET liver metastases is important in managing hormonal or carcinoid symptoms and is imperative to improve patient survival. Treatment for liver-dominant disease is varied; delineating biomarkers that may predict response will allow for better patient stratification.

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Section: Discussionmentioning

confidence: 99%

Neuroendocrine Tumors: Genomics and Molecular Biomarkers with a Focus on Metastatic Disease

Alexander

Ziv

2023

Cancers

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“…Intriguingly, recent studies in endocrine cells reveal that chromatin modifications and epigenetic changes are more common in pancreatic NENs than in small intestinal NENs (Figure 4). 91,92 However, it is not known whether these same mechanisms occur in the Brunner's glands of the proximal duodenum. Thus, future studies aimed at defining tissue-specific factors that predispose MEN1 tissues to neuroendocrine transformation will be critical to deciphering the mechanisms of GEP-NEN pathogenesis.…”

Section: Protein Interactions and Transcriptional Regulationmentioning

confidence: 99%

MENIN‐mediated regulation of gastrin gene expression and its role in gastrinoma development

2023

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The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues.Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.

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“…Normally, the histone complex has one copy of H1, two copies of H2A, H2B, H3, and H4. A family of linker histones termed histone H1 is involved in chromatin maintenance, controlling gene expression, and chromatin-based DNA repair [ 73 ].…”

Section: Molecular Landscapementioning

confidence: 99%

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

Ciobanu

Martin

Herlea

et al. 2022

Cancers

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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.

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Epigenetic Regulation in Gastroenteropancreatic Neuroendocrine Tumors

Cited by 7 publications

References 136 publications

Neuroendocrine Tumors: Genomics and Molecular Biomarkers with a Focus on Metastatic Disease

Neuroendocrine Tumors: Genomics and Molecular Biomarkers with a Focus on Metastatic Disease

MENIN‐mediated regulation of gastrin gene expression and its role in gastrinoma development

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

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