DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.
In 1948, Mandel and Métais1 described the presence of cell-free nucleic acid (cfNA) in human blood for the first time. This attracted little attention in the scientific community and it was not until 1994 that the importance of cfNA was recognized as a result of the detection of mutated RAS gene fragments in the blood of cancer patients2, 3 (Timeline). In 1996, microsatellite alterations on cell-free DNA (cfDNA) were shown in cancer patients4, and during the past decade increasing attention has been paid to cfNAs (such as DNA, mRNA and microRNAs (miRNAs)) that are present at high concentrations in the blood of cancer patients (Fig. 1). Indeed, their potential value as blood biomarkers was highlighted in a recent editorial in the journal Science5.
Figure 1 | Cell-free nucleic acids in the blood.
Mutations, methylation, DNA integrity, microsatellite alterations and viral DNA can be detected in cell-free DNA (cfDNA) in blood. Tumour-related cfDNA, which circulates in the blood of cancer patients, is released by tumour cells in different forms and at different levels. DNA can be shed as both single-stranded and double-stranded DNA. The release of DNA from tumour cells can be through various cell physiological events such as apoptosis, necrosis and secretion. The physiology and rate of release is still not well understood; tumour burden and tumour cell proliferation rate may have a substantial role in these events.
In 1948, Mandel and Métais1 described the presence of cell-free nucleic acid (cfNA) in human blood for the first time. This attracted little attention in the scientific community and it was not until 1994 that the importance of cfNA was recognized as a result of the detection of mutated RAS gene fragments in the blood of cancer patients2, 3 (Timeline). In 1996, microsatellite alterations on cell-free DNA (cfDNA) were shown in cancer patients4, and during the past decade increasing attention has been paid to cfNAs (such as DNA, mRNA and microRNAs (miRNAs)) that are present at high concentrations in the blood of cancer patients (Fig. 1). Indeed, their potential value as blood biomarkers was highlighted in a recent editorial in the journal Science5.
Figure 1 | Cell-free nucleic acids in the blood.
Mutations, methylation, DNA integrity, microsatellite alterations and viral DNA can be detected in cell-free DNA (cfDNA) in blood. Tumour-related cfDNA, which circulates in the blood of cancer patients, is released by tumour cells in different forms and at different levels. DNA can be shed as both single-stranded and double-stranded DNA. The release of DNA from tumour cells can be through various cell physiological events such as apoptosis, necrosis and secretion. The physiology and rate of release is still not well understood; tumour burden and tumour cell proliferation rate may have a substantial role in these events.
Individual tumour types can release more than one form of cfDNA.
Detecting cfNA in plasma or serum could serve as a 'liquid biopsy', which would be useful for numerous diagnostic applications and would avoid the need for tumour tissue biopsies. Use of such a liquid biopsy delivers the possibility of taking repeated blood samples, consequently allowing the changes in cfNA to be traced during the natural course of the disease or during cancer treatment. However, the levels of cfNA might also reflect physiological and pathological processes that are not tumour-specific6. cfNA yields are higher in patients with malignant lesions than in patients without tumours, but increased levels have also been quantified in patients with benign lesions, inflammatory diseases and tissue trauma7. The physiological events that lead to the increase of cfNA during cancer development and progression are still not well understood. However, analyses of circulating DNA allow the detection of tumour-related genetic and epigenetic alterations that are relevant to cancer development and progression. In addition, circulating miRNAs have recently been shown to be potential cancerbiomarkers in blood.
This Review focuses on the clinical utility of cfNA, including genetic and epigenetic alterations that can be detected in cfDNA, as well as the quantification of nucleosomes and miRNAs, and discusses the relationshipbetween cfNA and micrometastatic cells.
This Review focuses on the clinical utility of cfNA, including genetic and epigenetic alterations that can be detected in cfDNA, as well as the quantification of nucleosomes and miRNAs, and discusses the relationshipbetween cfNA and micrometastatic cells.
