The Triple-Code Model for Pancreatic Cancer: Cross Talk Among Genetics, Epigenetics, and Nuclear Structure

Abstract

Pancreatic adenocarcinoma is painful, generally incurable, and frequently lethal. The current progression model indicates that this cancer evolves by mutations and deletions in key oncogenes and tumor suppressor genes. This article describes an updated, more comprehensive model that includes concepts from the fields of epigenetics and nuclear architecture. Widespread use of next-generation sequencing for identifying genetic and epigenetic changes genome-wide will help identify and validate more and better markers for this disease. Epigenetic alterations are amenable to pharmacologic manipulations, thus this new integrated paradigm will contribute to advance this field from a mechanistic and translational point of view.

Keywords: Epigenetics; Pancreatic adenocarcinoma; Triple-code hypothesis.

Figure 1. Crosstalk between Genetics, Epigenetics, and Nuclear Structure in a Revised Comprehensive Progression Model for Pancreatic Cancer

Our model for the progression of pancreatic cancer incorporates the genetic events described in the previous model as well as epigenetic changes and other alterations caused by changes in nuclear shape. Importantly, this model integrates the concept that these alterations do not occur in isolation, rather genetic alterations crosstalk with epigenetic and nuclear structure changes to give rise to neoplastic transformation, as well as most features of the cancer phenotype and its symptoms.

Figure 2. Integration of Instructions from Genetics, Epigenetics and Nuclear Architecture into the “Triple Code Hypothesis”

Our comprehensive model for the development and progression of PDAC is based upon our understanding that gene expression networks are regulated by the combination of instructions dictated by genetics, epigenetics and nuclear architecture, which we have coined the “Triple Code Hypothesis”. Alterations in the Genetic Code form the foundation of the well-known DNA-centric hypothesis for the establishment and maintenance of the cancer phenotype, which includes mutations and deletions. The Epigenetic Code takes into account changes in DNA methylation, non-coding RNA molecules, and chromatin via histone modifications and the writers, readers, and erasers of the Histone Code. Finally, the Nuclear Structure Code, which includes the nuclear matrix and higher-order chromatin organization, impacts the fidelity of genome replication, chromatin organization, as well as gene expression.