By Marc Aurèle Chay

http://www.genengnews.com/gen-news-highlights/pan-cancer-epigenetic-signature-readable-in-circulating-tumor-dna/81252334

http://www.genengnews.com/gen-news-highlights/pan-cancer-epigenetic-signature-readable-in-circulating-tumor-dna/81252334

In Canada, screening for colorectal cancer can be done using the FOBT or FIT tests. These currently have suboptimal diagnostic accuracy, which is why researchers are investigating other avenues for non-invasive detection of early CRC. Scientists have found that in many early-stage cancers, including CRC, epigenetic alterations are present in much higher frequency than genetic mutations. As such, DNA methylation, ncRNAs, histone modifications are being investigated for potential diagnostic and prognostic markers of CRC.

DNA Methylation Biomarkers

Blood, stool, saliva and urine are being examined by the research community for these markers. DNA methylation in particular is being studied extensively, and some groups have reported sensitivities of 90-95% with specificity ranges of 85-94% for certain biomarkers in CRC. Some genes have risen to be the most promising markers, including the tumor specific M2 isoform of pyruvate kinase (PKM2), tissue inhibitor of matrix metalloproteinase 1 (TIMP1), vimentin (VIM) and septin 9 (SEPT9). DNA methylation is also being investigated for prognostic biomarkers and predictive markers for response to treatment. In particular, CpG island methylator phenotype (CIMP) positive cancers are found to correlate strongly with overall unfavorable prognosis, but seem to benefit from 5-FU based adjuvant chemotherapy. Hypermethylated Transcription Factor AP-2 Epsilon (TFAP2E) seems to also predict response to 5-FU based chemotherapy.

Histone Modification Biomarkers

Diagnostic and prognostic biomarkers using histone modifications have been much less studied, partly due to technical limitations of assays that are used to characterize the chromatin landscape. Some studies show acetylation of H3 lysine 56 and di- or tri-methylation of H3 lysine 9 and 27 have potential to be prognostic markers in CRC. These results are still currently preliminary and are expected to be further explored with the new bioinformatic tools and next-generation sequencing technologies that are being optimized.

Non-Coding RNA Biomarkers

On the other hand, non-coding RNAs, and in particular miRNAs, have triggered a substantial interest from the scientific community. Blood and stool based biomarkers have been investigated, and multiple candidates such as miR-21, miR-92a, miR17-3p or miR-106a have come up as potential diagnostic markers. MiR-21 has also been associated with poor patient survival, and several other miRNAs have been proposed as prognostic markers. As research evolves, scientists hope to engineer a panel of biomarkers that will be able to accurately identify and predict prognosis for early stage CRCs.

Epigenetics has offered us new tools to understand the complex etiology of colorectal cancer. As the scientific community further elucidates the mechanisms at play, epigenetic biomarkers to diagnose, classify and predict prognosis of CRC are also uncovered. Further research on these biomarkers may provide us with high performance assays that can be used to prevent and better manage patients with CRC.

References

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Okugawa, Y., Grady, W.M., Goel, A., 2015. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterology 149, 1204–1225.e12. doi:10.1053/j.gastro.2015.07.011

Rozalski, R., Gackowski, D., Siomek-Gorecka, A., Banaszkiewicz, Z., Olinski, R., 2016. Urinary Measurement of Epigenetic DNA Modifications: A Non-Invasive Assessment of the Whole-Body Epigenetic Status in Healthy Subjects and Colorectal Cancer Patients. ChemistryOpen 5, 550–553. doi:10.1002/open.201600103

Sameer, A.S., Nissar, S., 2016. Epigenetics in diagnosis of colorectal cancer. Mol Biol Res Commun 5, 49–57.

Sazanov, A.A., Kiselyova, E.V., Zakharenko, A.A., Romanov, M.N., Zaraysky, M.I., 2016. Plasma and saliva miR-21 expression in colorectal cancer patients. J. Appl. Genet. doi:10.1007/s13353-016-0379-9