Role of Epigenetics in Pancreatic Ductal Adenocarcinoma

Figures & data

Figure 1. Epigenetic mechanism involved in pancreatic ductal adenocarcinoma progression.

(A) PDAC is characterized by various mutations, including those involved in regulating epigenetic mechanisms. (B) Numerous epigenetic signatures could potentially be utilized for applications including early diagnosis and the study of tumor progression, and could be used as prognostic or therapeutic markers.

PDAC: Pancreatic ductal adenocarcinoma.

Table 1. Alterations in epigenetic regulators and associated significance.

Gene lost or mutated in PDAC	Molecular function	Survival response in patients	Ref.
DNMT3a	DNA methyltransferase, involved in de novo DNA methylation	Decreased patient survival	[4]
ASXL1	Polycomb group protein; involved in gene transcriptional regulation and chromatin architecture maintenance	Decreased patient survival	[4]
TET2	Dioxygenase of 5-methylcytosine, demethylation of cytosines	Decreased patient survival	[4]
KDM6A	H3K27me3 demethylase and tumor suppressive role	Worse prognosis and reduced OS	[34]
ARID1A (6%)	Chromatin remodeler, gene transcriptional regulation	Decreased patient survival	[13,15]
SMARCB1	Loss of SMARCB1 drives a switch in pancreatic cancer cells toward a more aggressive phenotype	Decreased patient survival	[3,15,2335]
PBRM1	Chromatin remodeler, gene transcriptional regulation, tumor suppressive role	Studies awaited in PDAC for patient response; loss of expression correlates with worse prognosis in clear-cell renal carcinoma	[15,36,37

OS: Overall survival; PDAC: Pancreatic ductal adenocarcinoma.

Table 2. List of epigenetic therapies in clinical trials.

Clinical trial ID	Phase	Interventions
NCT04257448	I, II	Romidepsin (HDACi); azacitidine (methylation inhibitor); nab-paclitaxel; gemcitabine; durvalumab; lenalidomide;
NCT01845805	II	Azacitidine (methylation inhibitor); first-line chemotherapy after recurrence
NCT04896073	II	Minnelide
NCT04705818	II	Durvalumab; tazemetostat (EZH2i)
NCT02349867	I	Gemcitabine; sorafenib; vorinostat; 3D conformal radiation; therapy and modulated radiation therapy; RosetteSep; DEPfff
NCT03250273	II	Entinostat; nivolumab
NCT03878524	II, IIA, IIB, III, IV	Abemaciclib; abiraterone; afatinib; bevacizumab; bicalutamidep; bortezomib; cabazitaxel; cabozantinib; capecitabine; carboplatin; celecoxib; cobimetinib; copanlisib; dabrafenib; dacomitinib; darolutamide; dasatinib; doxorubicin; durvalumab; emtansine; enasidenib; entrectinib; enzalutamide; erlotinib; everolimus; fluorouracil; idelalisib; imatinib; ipilimumab; lenvatinib; leucovorin; lorlatinib; losartan; nab-paclitaxel; neratinib; nivolumab; olaparib; oxaliplatin; palbociclib; panobinostat; pembrolizumab; pertuzumab; ponatinib; regorafenib; ruxolitinib; sirolimus; sorafenib; sunitinib; trametinib; trastuzumab; tretinoin; vemurafenib; venetoclax; vismodegib; vorinostat

DEPfff: Dielectrophoretic field-flow fractionation; HDACi: Histone deacetylase inhibitor.

Data taken from [38].

Figure 2. Aberrant regulation of epigenetic mechanisms contributes to pancreatic ductal adenocarcinoma.

Mutation or abnormal functioning of writers, readers and erasers associated with the processes of DNA methylation and histone post-translational modifications can cause PDAC. Additionally, onco-miRNA and other ncRNAs can promote the disease. Finally, mutations in chromatin remodelers can further exacerbate PDAC.

PDAC: Pancreatic ductal adenocarcinoma.

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