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Review
. 2021 Feb 5:9:622459.
doi: 10.3389/fcell.2021.622459. eCollection 2021.

Epigenetic Landscape of Liquid Biopsy in Colorectal Cancer

Aitor Rodriguez-Casanova  1   2 , Nicolás Costa-Fraga  1 , Aida Bao-Caamano  1 , Rafael López-López  2   3   4 , Laura Muinelo-Romay  4   5 , Angel Diaz-Lagares  1   4
Affiliations
Review

Epigenetic Landscape of Liquid Biopsy in Colorectal Cancer

Aitor Rodriguez-Casanova et al. Front Cell Dev Biol. .

Abstract

Colorectal cancer (CRC) is one of the most common malignancies and is a major cause of cancer-related deaths worldwide. Thus, there is a clinical need to improve early detection of CRC and personalize therapy for patients with this disease. In the era of precision oncology, liquid biopsy has emerged as a major approach to characterize the circulating tumor elements present in body fluids, including cell-free DNA and RNA, circulating tumor cells, and extracellular vesicles. This non-invasive tool has allowed the identification of relevant molecular alterations in CRC patients, including some indicating the disruption of epigenetic mechanisms. Epigenetic alterations found in solid and liquid biopsies have shown great utility as biomarkers for early detection, prognosis, monitoring, and evaluation of therapeutic response in CRC patients. Here, we summarize current knowledge of the most relevant epigenetic mechanisms associated with cancer development and progression, and the implications of their deregulation in cancer cells and liquid biopsy of CRC patients. In particular, we describe the methodologies used to analyze these epigenetic alterations in circulating tumor material, and we focus on the clinical utility of epigenetic marks in liquid biopsy as tumor biomarkers for CRC patients. We also discuss the great challenges and emerging opportunities of this field for the diagnosis and personalized management of CRC patients.

Keywords: CTCs; biomarkers; circulating nucleic acids; colorectal cancer; epigenetics; extracellular vesicles; liquid biopsy; precision oncology.

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Conflict of interest statement

RL-L has received honoraria for participation in Advisory Boards from Roche, AstraZeneca, Merck, MSD, Bayer, BMS, Novartis, Janssen, Lilly, Pfizer and Leo; travel, accommodations and expenses from Pharmamar, Roche, BMS and Pierre Fabre; research funding from Roche and Merck; and is co-founder and shareholder in Nasasbiotech, S.L., Mtrap Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The epigenetic machinery. There are three fundamental epigenetic mechanisms, represented by (i) DNA modifications (methylation and hydroxymethylation), (ii) post-translational modifications of histones and nucleosome positioning, and (iii) non-coding RNAs. These epigenetic layers are highly interrelated among them and regulate gene expression of relevant biological processes in normal cells. However, these mechanisms can be deregulated in tumor cells leading to cancer development and progression. Me, methylation of histones; Ac, acetylation of histones; 5mC, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosine; C, cytosine; lncRNA, long non-coding RNA; miRNA, microRNA; circRNA, circular RNA. Created with BioRender.com.
Figure 2
Figure 2
Epigenetic biomarkers in liquid biopsy for precision oncology of CRC patients. Colorectal primary tumors and metastasis can release epigenetic biomarkers into different types of biological fluids. The disruption of these epigenetic mechanisms can be detected in circulating tumor cells (CTCs), nucleic acids (cNAs) and extracellular vesicles (cEVs), showing clinical relevance as therapeutic targets and tumor biomarkers for early detection, prognosis, monitoring, therapy selection, and evaluation of therapeutic response in CRC. The detection of these epigenetic biomarkers in liquid biopsy have a great value to personalize the management of CRC patients. CRC, colorectal cancer; CTCs, circulating tumor cells; cfDNA, cell-free DNA; ncRNAs, non-coding RNAs; MRD, minimal residual disease. Created with BioRender.com.
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