The role of DNA methylation in human pancreatic neuroendocrine tumours

Abstract

Pancreatic neuroendocrine tumours (PNETs) are the second most c ommon pancreatic tumour. However, relatively little is known about their tumouri genic drivers, other than mutations involving the multiple endocrine neoplasia 1 ( MEN1), ATRX chromatin remodeler, and death domain-associated protein genes, which are found in ~40% of sporadic PNETs. PNETs have a low mutational burden, thereby sug gesting that other factors likely contribute to their development, including epige netic regulators. One such epigenetic process, DNA methylation, silences gene transcriptio n via 5’methylcytosine (5mC), and this is usually facilitated by DNA methyltransferase enzymes at CpG-rich areas around gene promoters. However, 5’hydroxymethylcytosine, which is the first epigenetic mark during cytosine demethylation, and opposes the function of 5mC, is associated with gene transcription, although the significance of this remains unknown, as it is indistinguishable from 5mC when conventional bisulfite conversion techniques are solely used. Advances in array-based technologies have faci litated the investigation of PNET methylomes and enabled PNETs to be clustered by methylo me signatures, which has assisted in prognosis and discovery of new aberrantly regulated genes contributing to tumourigenesis. This review will discuss the bi ology of DNA methylation, its role in PNET development, and impact on prognostication and discovery of epigenome-targeted therapies.

Keywords

• epigenetics
• methylation
• multiple endocrine neoplasia type 1
• menin
• pancreatic neuroendocrine tumours
• hydroxymethylation