Review
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Sep 15, 2017; 9(9): 341-353
Published online Sep 15, 2017. doi: 10.4251/wjgo.v9.i9.341
Epigenetics of gastroenteropancreatic neuroendocrine tumors: A clinicopathologic perspective
Brendan M Finnerty, Katherine D Gray, Maureen D Moore, Rasa Zarnegar, Thomas J Fahey III
Brendan M Finnerty, Katherine D Gray, Maureen D Moore, Rasa Zarnegar, Thomas J Fahey III, Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, United States
Author contributions: Finnerty BM, Gray KD and Moore MD analyzed the data and interpreted data and wrote the manuscript; Zarnegar R and Fahey III TJ made critical revisions to data analysis and interpretation and gave final approval of the version of the article to be published.
Conflict-of-interest statement: There are no conflicts of interest to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Brendan M Finnerty, MD, Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, York Ave, Suite A1027, New York, NY 10065, United States. bmf9002@nyp.org
Telephone: +1-212-7465187 Fax: +1-212-7469948
Received: February 25, 2017
Peer-review started: February 27, 2017
First decision: June 12, 2017
Revised: June 27, 2017
Accepted: August 3, 2017
Article in press: August 4, 2017
Published online: September 15, 2017
Processing time: 197 Days and 23.9 Hours
Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEP-NET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microRNA and long non-coding RNA (lncRNA) differential expression profiles that are distinctive of GEP-NETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.

Keywords: Epigenetics; Carcinoid; Neuroendocrine; MicroRNA; Methylation; Histone modifications; Chromatin remodeling; LncRNA

Core tip: Herein, we describe a review of the literature addressing known epigenetic changes which are thought to lead to the development of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Through a variety of scientific works, methylation patterns, chromatin remodeling alterations, and microRNA and long non-coding RNA differential expression profiles have been identified and in many cases correlated with GEP-NET malignancy and clinical outcomes. This overview shows the strong foundation which exists and underlines the importance of future work to evaluate the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.