Role of Epigenetics in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, associated with poor survival outcomes. Lack of early diagnosis, resistance to conventional therapeutic treatments (including immunotherapy) and recurrence are some of the major hurdles in PDAC and contribute to its poor survival rate. While the risk of genetic predisposition to cancers is widely acknowledged and understood, recent advances in whole-genome and next-generation sequencing techniques have led to the acknowledgment of the role played by epigenetics, especially in PDAC. Epigenetic changes are heritable genetic modifications that influence gene expression without altering the DNA sequence. Epigenetic mechanisms (e.g., DNA methylation, post-translational modification of histone complexes and ncRNA) that result in reversible changes in gene expression are increasingly understood to be responsible for tumor initiation, development and even escape from immune surveillance. Our review seeks to highlight the various components of the epigenetic machinery that are known to be implicated in PDAC initiation and development and the feasibility of targeting these components to identify novel pharmacological strategies that could potentially lead to breakthroughs in PDAC treatment.

Plain language summary

Despite advances in detection and treatment, pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) remains one of the most aggressive malignancies known to mankind, with one of the lowest 5-year survival rates (11%). Due to the lack of distinctive symptoms and the tumors’ aggressive ability to metastasize quickly, more than 50% of patients miss the opportunity to seek treatment at an early stage. While the role of genetics in cancer is well known, it is only recently that efforts have been made in identifying the role of heritable changes, regulated by epigenetic mechanisms, in the initiation and metastasis of cancer in individuals. Epigenetics refers to the phenomenon of alteration of gene expression through modifications of the chromatin landscape by DNA methylation, histone modifications and chromatin remodeling (due to ncRNA etc.) which is known to contribute to tumor heterogeneity. By identifying the epigenomic landscapes of patients’ tumors, we can identify the components of the epigenetic machinery that influence PDAC initiation and development. These proteins and enzymes could be excellent targets for developing novel pharmacological strategies that could potentially lead to breakthroughs in PDAC treatment.

Keywords::

• epigenetic mechanism
• epigenetics
• pancreatic ductal adenocarcinoma
• translational medicine
• tumor heterogeneity

S Lavania is the corresponding author and responsible for writing, overall organization and editing of the manuscript. All authors contributed equally to the content of the manuscript.

Acknowledgments

The authors would like to acknowledge A Saluja, Professor of Surgery at the University of Miami, for his guidance and support.

Financial&competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.