Downregulation of 5‐hydroxymethylcytosine is an early event in pancreatic tumorigenesis

Abstract

Epigenetic alterations are increasingly recognized as important contributors to the development and progression of pancreatic ductal adenocarcinoma. 5‐hydroxymethylcytosine (5hmC) is an epigenetic DNA mark generated through the ten‐eleven translocation (TET) enzyme‐mediated pathway and is closely linked to gene activation. However, the timing of alterations in epigenetic regulation in the progression of pancreatic neoplasia is not well understood. In this study, we hypothesized that aberrant expression of ten‐eleven translocation methylcytosine dioxygenase 1 (TET1) and subsequent global 5hmC alteration are linked to early tumorigenesis in the pancreas. Therefore, we evaluated alterations of 5hmC and TET1 levels using immunohistochemistry in pancreatic neoplasms (n = 380) and normal ducts (n = 118). The study cohort included representation of the full spectrum of precancerous lesions from low‐ and high‐grade pancreatic intraepithelial neoplasia (n = 95), intraductal papillary mucinous neoplasms (all subtypes, n = 129), intraductal oncocytic papillary neoplasms (n = 12), and mucinous cystic neoplasms (n = 144). 5hmC and TET1 were significantly downregulated in all types of precancerous lesion and associated invasive pancreatic ductal adenocarcinomas compared with normal ductal epithelium (all p < 0.001), and expression of 5hmC positively correlated with expression of TET1. Importantly, downregulation of both 5hmC and TET1 was observed in most low‐grade precancerous lesions. There were no clear associations between 5hmC levels and clinicopathological factors, thereby suggesting a common epigenetic abnormality across precancerous lesions. We conclude that downregulation of 5hmC and TET1 is an early event in pancreatic tumorigenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy

“…The ten–eleven translocation (TET) family of α-ketoglutarate-dependent dioxygenases indirectly promotes DNA demethylation by hydroxylation of 5-methylcytocine to 5-Hydroxymethylcytocine [ 31 ]. Characterization of pancreatic pre-cancerous lesions from pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, intraductal event during pancreatic oncocytic papillary neoplasms, and mucinous cystic neoplasms by immunohistochemistry revealed that downregulation of 5-hydroxymethylcytocine and TET1 is an early carcinogenesis [ 32 ]. Moreover, CRISPR-Cas9-induced knockout of TET1 showed that TET1 suppress pancreatic cancer progression via inhibition of the Wnt pathway [ 33 ].…”

Epigenetic Dysregulation of 5-hydroxymethylcytosine in Well-Differentiated Pancreatic Neuroendocrine Tumors

“…Epigenetic modifiers such as DNA methylation and demethylation affect global gene expression and play an important role in the pathogenesis of various cancers. 12 A substantial decrease in the amount of 5-hmC has been reported in various types of cancer, including melanoma, brain, lung, breast, liver, prostate, colon, and pancreatic ductal cancers; 11,[13][14][15][16][17][18] however, the 5-hmC levels in pancreatic neuroendocrine neoplasms remain unknown. In the present study, the loss of 5-hmC expression was seen in PanNETs with aggressive biological behavior and was significantly associated with the presence of distant metastases, high Ki-67 proliferation index, and increased tumor size, corresponding to a higher T-stage.…”

Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment

“…43 Such epigenetic alterations also have been reported in precancerous PanIN and IPMN lesions. [44][45][46][47] Multiple studies have categorized the transcriptomes of human PDACs, with several unique subtyping schemes proposed. 26,28,[48][49][50][51] Integrated analyses of these data suggest that there are likely 2 distinct transcriptional subtypes of PDAC, termed classical and basal, with the basal phenotype enriched in metastases and correlated with a worse prognosis.…”