Importance of Colorectal cancer biomarkers in epigenetic alterations

By Avishek Majumder on December 14, 2018

Both genetic and epigenetic alterations can cause Colorectal cancer (Voyias, Patel and Arasaradnam, 2016). Epigenetic modifications are those direct DNA modifications that influence non-coding RNAs like DNA methylation, histone modification, and chromatin remodelling. The increase in research in the area of biomarkers has improvement in diagnosis, prognosis, and prediction of treatment response in the patients with colorectal cancer. This article presents the emerging roles of epigenetic modifications in the detection, prognosis, and prediction of treatment response for colorectal cancer.

Epigenetic factors causing colorectal cancer

Modifications that are mitotically heritable to chromosomes can alter the gene expressions without changing the DNA sequence (Voyias, Patel and Arasaradnam, 2016). Epigenetic mutations are caused by processes like DNA methylation, histone modification, and chromatin remodelling. Epigenetic events cause cancer due to inactivation of tumour suppressor genes, activation of oncogenes and alteration of imprinting patterns without genetic stability.

Genetic and epigenetic modifications causing colorectal cancer (Chen et al., 2013)
Genetic and epigenetic modifications causing colorectal cancer (Chen et al., 2014)

Genome-wide hypo-methylation in Colorectal cancer

In the case of colorectal cancer, genome-wide hypo-methylation can be observed along with the gene promoter associated hypermethylation. Genome-wide hypo-methylation is mainly caused by loss of methylation specifically in repetitive DNA sequences and genes. Hypo-methylation leads to genomic instability causing activation of normally silent regions which includes oncogenes. Hypermethylation can cause aberrant silencing of tumour suppressor genes, DNA repair genes, cell cycle control genes, apoptotic genes, and genes that prevent abnormal activity of developmental pathways. This mechanism leads to colorectal cancer development (Kondo and Issa, 2010).

Genetic and epigenetic changes causing Cancer and Cancer biomarker detection (Herceg and Hainaut, 2007)
Genetic and epigenetic changes causing Cancer and Cancer biomarker detection (Herceg and Hainaut, 2007)

Epigenetic biomarkers for Colorectal cancer

Biomarkers for colorectal cancer can be of genetic as well as an epigenetic molecular basis. Therefore, they can be exploited for screening, early detection, diagnosis, prediction and prognosis of the disease. The individual with an increased risk of colorectal cancer can be identified with the help of cancer-specific mutations and abnormal epigenetic modification to select optimal interventions (Choong and Tsafnat, 2012). Thus, with this molecular knowledge, a sensitive and non-invasive method for cancer detection and diagnosis may be developed leading to drug discovery.

Epigenomic Biomarkers (Greenberg et al., 2014)
Epigenomic Biomarkers (Greenberg et al., 2014)

DNA methylation as an epigenetic biomarker

DNA methylation occurs early in the development of colorectal cancer. Methylation targets are the most promising epigenetic alterations in colorectal cancer. Again, studies have found out that there are hyper-methylation and hypo-methylation in colorectal cancer that indicates the down-regulation and up-regulation of the genes during the progression of colorectal cancer. These genes include MGMT, CDKN2A, and BAGE. They play a vital role in the initiation and progression of colorectal cancer. Furthermore, the identification of these genes and the detection of mutation in them lead to the discovery of biomarkers (Zhu and Yao, 2009).

DNA-methylation as epigenetic biomarker (Syn, Blackwell and Jamieson, 2016)
DNA-methylation as an epigenetic biomarker (Syn, Blackwell and Jamieson, 2016)

Detection of Colorectal cancer using biomarkers

In the case of colorectal cancer, stool samples used for early detection and testing. As the tumour markers are likely to enter the stool that blood or urine of the patients. So, a noninvasive technique like stool DNA test provides results with high specificity. However, biomarkers that are detected in stool tests are HIC1, SFRP2, and TFP12. Biomarkers for plasma samples will provide a better specificity than the stool biomarkers. Epigenetic biomarkers present in plasma are CDKN2A, TMEFF2, NGFR, and SEPT9. Also in recent studies, along with the genetic alterations and genomic instability, the epigenetic alterations play a crucial role in driving tumour onset. This further allows the progression of colorectal cancer that helps in the identification  (Kim, Lee, and Sidransky, 2010).

Epigenetic markers are potent diagnostic, prognostic and predictive biomarkers for colorectal cancer. But also, it is a potential pharmacological target due to its reversible nature. Normally, DNA methylation and histone modification act as targeted drug therapies. An agent that aims to reactivate dormant tumour suppressor genes by inhibiting DNMT and histone deacetylase consists of anti-tumour activity. There is no single biomarker that can universally detect or predict cancer or treatment regime for colorectal cancer. Therefore, a combination of multiple genetic and epigenetic markers is needed. In future, these biomarkers will be able to guide the treatment election, thus individualizing the medicine for colorectal cancer patients.


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