Epigenetics of gastroenteropancreatic neuroendocrine tumors: A clinicopathologic perspective

Table 1 Overview of epigenetic mechanisms

Mechanism	Effect	Regulation	Ref.
DNA Methylation		DNMTs
Hypomethylation	Chromosomal instability, reactivation of transposable elements, loss of imprinting		[12]
Hypermethylation	Inactivation of tumor suppressor genes		[12]
Histone modification		HDACs, histone methyltransferases
Lysine acetylation	Transcription activation		[12]
Methylation	Transcription activation or suppression		[12]
Noncoding RNAs		Variable
LncRNAs	Pre-transcriptional regulation		[17]
MiRNAs	Post-transcriptional binding to 3’-untranslated regions to inhibit translation or promote mRNA degradation		[18]

DNMTs: DNA methyltransferase enzymes; HDACs: Histone acetyltransferases and deacetylases; LncRNA: Long non-coding RNA.

Table 2 Methylation profiles in neuroendocrine tumors

Modification	Gene	Gene function	Clinical effect	Tumor	Ref.
Hypermethylation (Inactivation)
	RASSF1	Induces cell cycle arrest	Correlated with malignancy, levels highest in metastases	PNET > GI-NET	[32-34]
	INK4a/p16	Induces cell cycle arrest and apoptosis	Decreased 5-yr survival, liver metastases	PNET, gastrinoma	[38,39]
	MGMT	DNA repair	Improved response to temozolomide	PNET	[32]
	TIMP-3	Inhibits metalloproteinases	Correlated with metastases	PNET	[44]
	UCHL-1	Post-translational modifier, de-ubiquitinates proteins marked for lysosomal degradation	Correlated with metastases	GEP-NET	[45-47]
	IGF2	Chromatin packaging	Specific for insulinomas, increased stage	Insulinoma	[51]
	MLH1	DNA repair	Correlated with malignancy	PNET, insulinoma	[52]
Global hypomethylation
	LINE-1	Repeating long interspersed nucleotide elements	Correlated with malignancy and lymph node metastases	Ileal NET > GEP-NET	[53-55]
	Alu	Repeating long interspersed nucleotide elements	Correlated with malignancy	GEP-NET	[54]

GEP-NETs: Gastroenteropancreatic neuroendocrine tumors; PNETs: Pancreatic tumors; GI-NETs: Gastrointestinal tumors.