Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the 3rd most common malignant neoplasm worldwide, with more than two million new cases diagnosed yearly. Despite increasing efforts in screening, many cases are still diagnosed at a late stage, when mortality is high. This paper briefly reviews known genetic causes of CRC (distinguishing between sporadic and familial forms) and discusses potential and confirmed nucleic acid biomarkers obtainable from liquid biopsies, classified by their molecular features, focusing on clinical relevance. We comment on advantageous aspects such as better patient compliance due to blood sampling being minimally invasive, the possibility to monitor mutation characteristics of sporadic and hereditary CRC in a disease showing genetic heterogeneity, and using up- or down-regulated circulating RNA markers to reveal metastasis or disease recurrence. Current difficulties and thoughts on some possible future directions are also discussed. We explore current evidence in the field pointing towards the introduction of personalized CRC management.

Keywords: biomarkers; cell-free nucleic acids; colorectal cancer; liquid biopsy; non-invasive diagnosis.

Figure 1

Origin of extracellular nucleic acids in circulation. Tumor cells release extracellular cfNAs through a combination of (i) cell death such as apoptosis, necrosis, and netosis or (ii) active secretion. Circulating bacterial DNA (cbDNA) may also be detected in blood samples from cancer patients. The loss of membrane integrity in necrosis results in releasing intracellular contents, including fragments of DNA, into the circulation. In netosis, activated neutrophils release neutrophil extracellular traps, webs of chromatin, and mitochondrial DNA (mtDNA). cfDNA may exist in the peripheral blood as either free or linked to proteins in the form of nucleosomal DNA, or associated with extracellular membrane vesicles (EMVs) such as exosomes or microvesicles secreted by cells. Methylated DNA and various types of RNA are present as well (created with Biorender.com, accessed on 21 July 2022).