Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer

Abstract

Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer-related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the precancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and precancer, determination of the prognosis of cancer and prediction of the response to therapy. Epigenetic alterations have emerged as one of most robust classes of biomarkers and are the basis for a growing number of clinical tests for cancer screening and surveillance.

Keywords: Barrett’s Esophagus; Biomarkers; Chromatin; Colorectal Cancer; DNA; Diagnosis; Esophageal Cancer; Gastric Cancer; Histone; Methylation; Noncoding RNA; Pancreatic Cancer; Predictive; Prognosis; Treatment.

Figure 1:

Schematic diagram showing factors that influence epigenetic alteration formation and the timing of epigenetic alteration formation in GI tract cancer formation.

Figure 2A and B:

Schematic diagram of DNA hypermethylation and DNA hypomethylation in cancer. (TF-1=transcription factor 1, TF-2=transcription factor 2, TF-3=transcription factor 3, RNA pol II=RNA polymerase II, HDAC=histone deacetylase complex, DNMT=DNA methyltransferase, MBP=methyl binding protein, Onco miRNA=oncogenic microRNA. CpG shores are the regions immediately flanking CpG islands (CGI), and they can be methylated just as CpG islands can be. The consensus definition of a CpG shore is up to 2kbp away from the CpG island. miRNA silencing refers to hypermethylation of microRNA loci that silence miRNA expression, which can suppress tumor suppressor miRNAs or increase the expression of inactivated oncogenes that are the targets of the miRNAs Figure 2C: Schematic diagram of DNA chromatin structure and histone modification states that affect conformation of chromatin. (H2A=histone 2A, H2B=histone 2B, H3=histone 3, H4=histone 4, ub=ubiquitylated, me=methylated, Ac=acetylated, K=lysine. Onco miR is an oncogenic microRNA.)

Figure 3:

Diagram showing the polyp-to-CRC progression sequence and associated methylated gene alterations that have been shown to be potential or clinically used polyp and CRC detection markers or prognostic markers. The prefix “m” designates the methylated gene. mEVL and mMLH1 are used as tissue based biomarkers, whereas mVIM, mNDRG4, and mBMP3 are stool based biomarkers. mSEPT9 is a blood-based biomarker.