Epigenetic reprogramming in pancreatic premalignancy and clinical implications

Abstract

Pancreatic cancer (PC) is the most lethal human cancer, with less than 10% 5-year survival. Pancreatic premalignancy is a genetic and epigenomic disease and is linked to PC initiation. Pancreatic premalignant lesions include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), with pancreatic acinar-to-ductal metaplasia (ADM) as the major source of pancreatic premalignant lesions. Emerging evidence reveals that an epigenetic dysregulation is an early event in pancreatic tumorigenesis. The molecular mechanisms of epigenetic inheritance include chromatin remodeling; modifications in histone, DNA, and RNA; non-coding RNA expression; and alternative splicing of RNA. Changes in those epigenetic modifications contribute to the most notable alterations in chromatin structure and promoter accessibility, thus leading to the silence of tumor suppressor genes and/or activation of oncogenes. The expression profiles of various epigenetic molecules provide a promising opportunity for biomarker development for early diagnosis of PC and novel targeted treatment strategies. However, how the alterations in epigenetic regulatory machinery regulate epigenetic reprogramming in pancreatic premalignant lesions and the different stages of their initiation needs further investigation. This review will summarize the current knowledge of epigenetic reprogramming in pancreatic premalignant initiation and progression, and its clinical applications as detection and diagnostic biomarkers and therapeutic targets in PC.

The cross-talk between the macro and micro-environment in precursor lesions of pancreatic cancer leads to new and promising circulating biomarkers

“…Furthermore, miR-483-3p is upregulated in PanIN, and its expression levels correlate with the progression of PanIN. Notably, circulating levels of miR-483-3p are significantly elevated in the serum and serum exosomes of patients with PC, confirming the evidence demonstrated by Abue et al Interestingly, serum levels of miR-483-3p were shown to be able to effectively differentiate between patients with early stage PC (≤ 2 cm) and healthy controls [ 139 ]. Finally, a targeted study of exosomal miRNA profiles in early lesions and cancer showed differential expression of miRNA-196b-3p and miRNA-204-3p between IPNM, MCN and PC.…”

“…Other nucleic acids that are proving to be interesting biomarkers include circulating microRNA and lncRNA, which are tumor (and PC) specific and can be easily detected in the circulation of patients as potential diagnostic biomarkers of malignancy [ 138 ]. Even if the study of miRNA deregulation was well characterized as a very early event in the progression of PC and several miRNAs were identified to be involved in PanIN, IPMN and MCM progression, only a few of them were applied stepwise as biomarkers in plasma patients [ 139 ]. Interestingly, Lui J and colleagues evaluated the possibility of combining the plasma miRNA dosage with the early detection of CA-19–9, and claimed that the combination of CA19-9, miR-16, and miR-196a in the plasma is more effective in distinguishing PC from non-PC patients (normal or chronic pancreatitis), especially in early tumor screening [ 130 ].…”

“…For instance, in the NCT03432624 and NCT04584996 clinical trials, efforts have been made to enhance PC diagnosis by integrating the detection of microRNAs, traditional tumor markers, and imaging techniques. NCT04406831 investigates the significance of certain blood born miRNAs for early PC diagnosis, treatment response prediction, and prognostic insights in patients [ 139 ]. Moreover, the NCT04636788 clinical trial is looking for circulating extracellular exosomal small RNA in blood samples from healthy individuals and those with early lesions to obtain more suitable results ( Table 1 ) .…”