English Katherine A, Thakker Rajesh V, Lines Kate E
OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
Endocr Oncol. 2023 Apr 17;3(1):e230003. doi: 10.1530/EO-23-0003. eCollection 2023 Jan 1.
Pancreatic neuroendocrine tumours (PNETs) are the second most common pancreatic tumour. However, relatively little is known about their tumourigenic drivers, other than mutations involving the multiple endocrine neoplasia 1 (, ATRX chromatin remodeler, and death domain-associated protein genes, which are found in ~40% of sporadic PNETs. PNETs have a low mutational burden, thereby suggesting that other factors likely contribute to their development, including epigenetic regulators. One such epigenetic process, DNA methylation, silences gene transcription 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 facilitated the investigation of PNET methylomes and enabled PNETs to be clustered by methylome signatures, which has assisted in prognosis and discovery of new aberrantly regulated genes contributing to tumourigenesis. This review will discuss the biology of DNA methylation, its role in PNET development, and impact on prognostication and discovery of epigenome-targeted therapies.
胰腺神经内分泌肿瘤（PNETs）是第二常见的胰腺肿瘤。然而，除了约40%的散发性PNETs中发现的涉及多发性内分泌肿瘤1型、ATRX染色质重塑因子和死亡结构域相关蛋白基因的突变外，人们对其肿瘤发生驱动因素了解相对较少。PNETs的突变负担较低，因此表明其他因素可能促成其发生发展，包括表观遗传调节因子。DNA甲基化就是这样一种表观遗传过程，它使基因转录沉默，产生5 - 甲基胞嘧啶（5mC），这通常由基因启动子周围富含CpG区域的DNA甲基转移酶催化。然而，5 - 羟甲基胞嘧啶作为胞嘧啶去甲基化过程中的首个表观遗传标记，与5mC的功能相反，它与基因转录相关，尽管其意义仍不明确，因为仅使用传统亚硫酸氢盐转化技术时，它与5mC无法区分。基于阵列技术的进展促进了对PNET甲基化组的研究，并使PNETs能够根据甲基化组特征进行聚类，这有助于预后评估以及发现有助于肿瘤发生的新的异常调控基因。本综述将讨论DNA甲基化的生物学特性、其在PNET发生发展中的作用，以及对预后评估和表观基因组靶向治疗发现的影响。
