ReviewGenetics and Genetic TestingEpigenetic Alterations in Colorectal Cancer: Emerging Biomarkers
Section snippets
Overview of DNA Methylation in Cancer
The most widely studied epigenetic alteration in cancer is aberrant DNA methylation. Although DNA hypermethylation has received the most attention recently, DNA hypomethylation was the first reported DNA methylation abnormality in human cancer (1983).5 As illustrated in Figure 1, at this time global DNA hypomethylation was identified in both colorectal adenomas and CRC.6 It was not until several years later, that Baylin and colleagues identified site-specific hypermethylation of the calcitonin (
Histone Modifications: a Potential Class of CRC Biomarkers
DNA in eukaryotic cells is found in chromatin, which is a complex of macromolecules consisting of DNA, RNA and protein. The primary functions of chromatin are to facilitate DNA compaction, to reinforce the DNA macromolecule during mitosis, to protect against DNA damage, and to control gene expression and DNA replication. The primary protein components of chromatin are histones, which regulate DNA compaction and gene expression. Histones are protein octamers that consist of two copies of four
Noncoding RNA Overview
The central dogma of molecular biology, which describes the sequential transfer of genetic information and the concept that “DNA makes RNA and RNA makes protein”, was developed in 1956 and provided a fundamental framework for modern molecular biology until recently.159 Advances in our understanding of the regulation of gene expression has been provided by the Encyclopedia of DNA Elements Consortium (ENCODE) transcriptome project, which recently revealed that protein-coding genes represent less
Conclusion and Perspectives
Advances in our understanding of the natural history of CRC and the epigenetics of colon polyps and CRC has led to the development of epigenetic biomarker assays for CRC diagnosis, prognosis, and prediction of treatment response (Figure 3). The last two decades of research have demonstrated the potential of aberrant DNA methylation and alterations in noncoding RNAs to be used as biomarkers for colon polyps and CRC. Continued investigation of these promising class of biomarkers promises to lead
Acknowledgements
We thank Drs Shusuke Toden, Wenhao Weng and Timothy Zumwalt, from the Center for Gastrointestinal Research for their advice, suggestions, and tireless efforts in editing and improving the overall quality of this article. We also thank R.A.C.E. Charities for their inspiration and support in biomarker development studies (WMG).
References (50)
- et al.
A genetic model for colorectal tumorigenesis
Cell
(1990) - et al.
CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability
Gastroenterology
(2002) - et al.
Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer
Gastroenterology
(2005) - et al.
CpG island methylation in aberrant crypt foci of the colorectum
Am J Pathol
(2002) - et al.
Sialic acid and epithelial differentiation in colorectal polyps and cancer—a morphological, mucin and lectin histochemical study
Pathology
(1992) - et al.
Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths
CA Cancer J Clin
(2011) The epigenotype
Endeavour
(1942)DNA methylation patterns and epigenetic memory
Genes Dev
(2002)- et al.
Hypomethylation distinguishes genes of some human cancers from their normal counterparts
Nature
(1983) - et al.
Hypomethylation of DNA from benign and malignant human colon neoplasms
Science
(1985)
DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas
Cancer Res
Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma
Hum Genet
Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene
Am J Hum Genet
CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene
Oncogene
Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers
Cancer Res
Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines
Cancer Res
Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas
Proc Natl Acad Sci U S A
Gene silencing in cancer in association with promoter hypermethylation
N Engl J Med
Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome
Nat Genet
Number of CpG islands and genes in human and mouse
Proc Natl Acad Sci U S A
Comprehensive analysis of CpG islands in human chromosomes 21 and 22
Proc Natl Acad Sci U S A
Analysis of promoter CpG island hypermethylation in cancer: location, location, location!
Clin Cancer Res
Cancer epigenetics reaches mainstream oncology
Nat Med
Epigenetic gene silencing in cancer: the DNA hypermethylome
Hum Mol Genet
Proteins that bind methylated DNA and human cancer: reading the wrong words
Br J Cancer
Cited by (552)
Aberrant H3K4me3 modification of immune response genes in CD4<sup>+</sup> T cells of patients with systemic lupus erythematosus
2024, International ImmunopharmacologyPotential biomarkers: The hypomethylation of cg18949415 and cg22193385 sites in colon adenocarcinoma
2024, Computers in Biology and MedicineTumor circulating biomarkers in colorectal cancer
2024, Cancer Treatment and Research CommunicationsSmall-molecule drugs of colorectal cancer: Current status and future directions
2024, Biochimica et Biophysica Acta - Molecular Basis of DiseaseChromatin factors: Ready to roll as biomarkers in metastatic colorectal cancer?
2023, Pharmacological Research
Conflicts of interest Dr Grady has limited ownership interest in a patent application for methylated MLH1. Drs Okugawa and Goel disclose no conflicts relevant to this work to report.
Funding This work was supported by National Institutes of Health/National Cancer Institute grants R01 CA72851, CA181572, CA184792, and U01 CA187956, a Charles A Sammons Cancer Center pilot grant, the Baylor Research Institute (A.G.), NIH grants P30CA15704, UO1CA152756, R01CA194663, U54CA143862, and P01CA077852, the RACE Charities, and a Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (W.M.G.).