Review
Genetic and Epigenetic Biomarkers of Colorectal Cancer

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Cancer is a heterogeneous disease caused, in part, by genetic and epigenetic alterations. These changes have been explored in studies of the pathogenesis of colorectal cancer (CRC) and have led to the identification of many biomarkers of disease progression. However, the number of biomarkers that have been incorporated into clinical practice is surprisingly small. We review the genetic and epigenetic mechanisms of colorectal cancer and discuss molecular markers recommended for use in early detection, screening, diagnosis, determination of prognosis, and prediction of treatment outcomes. We also review important areas for future research.

Section snippets

Genetic Factors

Approximately a century ago, von Hansemann10 reported abnormal mitoses in cancer cells. Theodor Boveri11 observed that the abnormal condition of chromosomes in sea urchins contributes to tumor formation and proposed that chromosomal abnormalities are fundamental to cancer. Since then, genetic factors have been in the mainstream of cancer research and the expansion of knowledge in this area has improved our understanding of cancer.

Genetic mutations include small changes in nucleotide sequences

Epigenetic Factors

Epigenetic mutations are mitotically heritable modifications to chromosomes that alter gene expression without changing the DNA sequence.20 The processes involved in epigenetics are DNA methylation, histone modification, and chromatin remodeling. Epigenetics was introduced by CH Waddington in 1939,21 and its association with cancer was first published in 1983.22 Many properties of cancer cells, eg, tumor cell heterogeneity and resistance to therapy23 are not explained by genetic events alone.

Biomarkers in Clinical Use

Genetic and epigenetic alterations can be exploited as biomarkers for screening, early detection, diagnosis, prediction, and prognosis. Cancer-specific mutations and abnormal epigenetic modifications can be used to identify individuals at increased risk and to select optimal interventions. Sensitive and noninvasive methods for cancer detection and diagnosis may be developed from molecular knowledge. Drug discovery is driven by molecular knowledge and the metabolic and signaling pathways

Recent Progress in Biomarker Discovery

Independent investigations of several candidate biomarkers show contradicting results. These may be due to a publication bias, lack of standardization, unintended statistical biases in the samples,9 or clinical trials being conducted on heterogeneous patient groups where treatment is likely to be tailored according to the molecular pathology of the cancer.

Conclusion

The promise of personalized medicine is now a reality.61 With the plethora of studies on different genetic and epigenetic markers for diagnosis, prediction, therapeutic decisions, and prognosis, the translation of molecular genetics is a great challenge. Rapid approval of multiple active agents and speedy proposals of new biomarkers and assays have complicated the translational process.47, 73 No single molecular marker can universally detect or predict cancer or treatment regimen.91 Combining

Acknowledgments

The authors thank Dr Megan Hitchins for her critical comments.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Funding for this work was provided by Cure Cancer Australia Foundation Grant with assistance from Cancer Australia and awarded through the 2009 round of the Priority-driven Collaborative Cancer Research Scheme (630435) and a New South Wales Health Capacity Building Infrastructure Grant.

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