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Colorectal Cancer Epigenetics
Background

In a recent issue of the Journal of Clinical Oncology, van Engeland and colleagues published a comprehensive review of colorectal cancer (CRC) epigenetics.1 Epigenetics is a rapidly emerging field of study and, following a consensus meeting in December 2008, is defined as “an epigenetic trait is a stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequence.”2, p.781 van Engeland and colleagues have also proposed three categories of signals that operate in the establishment of a stably heritable epigenetic state. The first is a signal from the environment, the second is a responding signal in the cell that specifies the affected chromosomal location, and the third is a sustaining signal that perpetuates the chromatin change in subsequent generations.2 van Engeland et al review CRC carcinogenesis, noting that approximately 15 mutations are thought to be functionally important during CRC carcinogenesis. Epigenetic alterations affect every component of gene regulation. The review traces the history of CRC genetics and epigenetics through a timeline from 1971 (two-hit hypothesis3) through 2009 (hypermethylation).

The most extensively characterized epigenetic alteration in CRC is promoter hypermethylation. Epigenetic alterations not only complement genetic alterations in the pathogenesis of CRC, but complex interactions between different DNA and chromatin modifications exist which characterize subgroups of CRC with distinct etiology and prognosis. The authors conclude, in order to prevent and treat CRC by interfering with altered epigenetic regulation of gene expression, our current lack of understanding of what causes and determines altered epigenetic regulation of gene expression in CRC epithelium and the surrounding stroma needs to be addressed. Although a causal role for genetic susceptibility and environmental factors has been proposed, independent population-based studies assessing the influence of genetic variation and environmental factors, such as diet and lifestyle, on epigenetic regulation of gene expression should be conducted to test these hypotheses. Only by considering the complex interactions of CRC genetics and epigenetics will there be more complete insight in CRC carcinogenesis that will allow translation of these findings to clinical practice.2

ManageCRC Commentary

Cancer has long been considered to be a disease caused by genetic mutations. Decades ago, Knudson suggested that multiple "hits" to DNA were necessary to cause cancer. Later discoveries of oncogenes and proto-oncogenes confirmed this theory and epigenetics has the potential to further characterize exactly what happens before cancer becomes evident. While some cancers have been definitively associated with specific mutations, others have yet to be fully characterized. van Engeland and colleagues present an admirable review of the complex issues of epigenetics and also discuss the use of epigenetics in the context of translational research. Use of epigenetic markers in CRC early detection requires further research before these methods can replace evidence-based interventions such as fecal occult blood or fecal DNA testing.

Epigenetic screening, prognostic and predictive markers have yet to be developed to the point of clinical utility, but the potential is there. Data from large scale gene expression profiling studies are needed to help uncover the biologically and clinically relevant relationships between genetics, epigenetics, and tumor behavior. Further research will lead to continued development of individualized therapy based on the molecular profile of an individual’s CRC. Validation of newly discovered and current markers in multiple, large, population-based studies and randomized clinical trials of CRC treatment using comparable techniques will be required to truly assess the clinical value.

References

  1. van Engeland M, Derks S, Smits KM, et al. Colorectal cancer epigenetics: Complex simplicity. J Clin Oncol. 2011; 29:1382-1391. doi: 10.1200/JCO.2010.28.2319 Link to abstract http://jco.ascopubs.org/content/early/2011/01/10/JCO.2010.28.2319.abstract 
  2. Berger SL, Kouzarides T, Shiekhattar R, et al. An operational definition of epigenetics. Genes Dev. 2009; 23:781-783. doi:10.1101/gad.1787609 Link to free full text http://genesdev.cshlp.org/content/23/7/781.full.pdf+html
  3. Knudson A. Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971; 68: 820–823. doi:10.1073/pnas.68.4.820 Link to abstract http://www.ncbi.nlm.nih.gov/pmc/articles/PMC389051/ 


Article Created On : 4/18/2011 10:26:58 AM             Article Updated On : 4/18/2011 10:26:58 AM