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Review
. 2022 Jul 20:12:943253.
doi: 10.3389/fonc.2022.943253. eCollection 2022.

Circulating Tumor DNA as a Cancer Biomarker: An Overview of Biological Features and Factors That may Impact on ctDNA Analysis

Estela Sánchez-Herrero  1   2 , Roberto Serna-Blasco  1 , Lucia Robado de Lope  1 , Víctor González-Rumayor  2 , Atocha Romero  1   3 , Mariano Provencio  1   3
Affiliations
Review

Circulating Tumor DNA as a Cancer Biomarker: An Overview of Biological Features and Factors That may Impact on ctDNA Analysis

Estela Sánchez-Herrero et al. Front Oncol. .

Abstract

Cancer cells release nucleic acids, freely or associated with other structures such as vesicles into body fluids, including blood. Among these nucleic acids, circulating tumor DNA (ctDNA) has emerged as a minimally invasive biomarker for tumor molecular profiling. However, certain biological characteristics of ctDNA are still unknown. Here, we provide an overview of the current knowledge about ctDNA biological features, including size and structure as well as the mechanisms of ctDNA shedding and clearance, and the physio-pathological factors that determine ctDNA levels. A better understanding of ctDNA biology is essential for the development of new methods that enable the analysis of ctDNA.

Keywords: biomarker; ctDNA kinetics; ctDNA= circulating tumor DNA; liquid biopsy; monitoring.

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Conflict of interest statement

Authors ES-H and VG-R were employed by Atrys Health. AR reports the following conflict of interest: Consulting or Advisory Role: Takeda, AstraZeneca. Research Funding: Bristol Myers Squibb Foundation (Inst), Boehringer Ingelheim (Inst), Takeda (Inst) Expert Testimony: Vivo Diagnostics. MP reports grants, personal fees, and travel expenses from BristolMyers Squibb, Roche, and AstraZeneca; and personal fees from Merck Sharpe & Dohme and Takeda, outside the submitted work. 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
ctDNA publications: Number of publications with ctDNA as a topic between 1990 and 2021, collected in Web of ScienceTM database.
Figure 2
Figure 2
Mechanisms of ctDNA release: Tumor cells shed DNA into the bloodstream by different types of cell death, including necrosis (larger fragments of >200 bp), apoptosis (shorter fragments of <200 bp enriched with tumor-derived genomic alterations), pyroptosis, phagocytosis, oncosis or ferroptosis, but also by non-death associated mechanisms such as senescence, or the active secretion of EVs and mtDNA. Thus, ctDNA analysis provides tumor-relevant clinical information.
Figure 3
Figure 3
Biological features of ctDNA: The integrated analysis of ctDNA somatic alterations, methylation and fragmentomic information, improves ctDNA detection and provides useful information about original tissue.
Figure 4
Figure 4
Mechanisms of ctDNA clearance: Kupffer cells from the liver are primarily responsible for ctDNA clearance, followed by circulating enzymes and immune system cells and other filtering organs such as kidneys, spleen and lymph nodes.
Figure 5
Figure 5
ctDNA amount in different cancer types: The amount of ctDNA is correlated with tumor type, size, stage and metastasis.
See this image and copyright information in PMC

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