Increased levels of circulating nucleic acids (DNA, mRNA and microRNA (miRNA)) in the blood reflect pathological processes, including malignant and benign lesions, inflammatory diseases, stroke, trauma and sepsis. During these processes nucleic acids are shed into the blood by apoptotic and necrotic cells.
In cancer patients, circulating DNA carries tumour-related genetic and epigenetic alterations that are relevant to cancer development, progression and resistance to therapy. These alterations include loss of heterozygosity (LOH) and mutations of tumour suppressor genes (such as TP53) and oncogenes (such as KRAS and BRAF).
Additional genetic alterations that are detectable on circulating DNA and used as biomarkers in cancer include the integrity of non-coding genomic DNA repeat sequences (such as ALU and LINE1). Although still in their infancy, DNA integrity assays have the potential to become a universal blood biomarker for multiple cancers.
Epigenetic alterations in genes (such as glutathione S-transferase P1 (GSTP1 and septin 9 (SEPT9)) and adenomatous polyposis coli (APC)) that are relevant to tumorigenesis and the progression of solid tumours have been detected on circulating DNA in cancer patients, and their potential clinical utility is indicated by the launch of commercial tests for cancer screening.
The detection of circulating nucleosomes in blood indicates that cell-free DNA (cfDNA) retains at least some features of the nuclear chromatin during the process of DNA release. Initial clinical studies have indicated that monitoring the abundance of nucleosomes has potential utility for monitoring the efficacy of therapy in cancer patients.
Dying tumour cells also discharge miRNAs, which circulate stably in the blood. The pivotal functions of miRNAs in cancer development and progression may explain the promising results of pilot studies on cancer patients using miRNA blood tests for tumour detection and prognosis.
The cellular source of tumour-derived circulating nucleic acids is still subject to debate. After complete removal of the primary tumour the detection of cfDNA may signal the presence of micrometastatic cells in distant organs, such as the bone marrow, which pose a risk of relapse.
Metastatic and primary tumours from the same patient can vary at the genomic, epigenomic and transcriptomic levels. Minimally invasive blood analyses of cell-free nucleic acid allow repetitive real-time monitoring of these events and will, therefore, gain clinical utility in the determination of prognosis and treatment efficacy.
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.
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Funding was provided by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, BMBF, Erich und Gertrud Roggenbuck-Stiftung, and the Sheldon and Miriam Adelson Foundation (to D.S.B.H.), the Melanoma Research Alliance (to D.S.B.H.), KOMEN BCTR0707528, CBCRP 16IB-0076 (to D.S.B.H.), and the US National Institutes of Health NCI R33, PO1 CA29605 and CA12582 (to D.S.B.H.).
The authors declare no competing financial interests.
Small non-coding RNA molecules that modulate the activity of specific mRNA molecules by binding and inhibiting their translation into polypeptides.
- Quantitative real-time clamp PCR assay
A technique that uses a peptide nucleic acid clamp and locked nucleic acid probes, which are DNA synthetic analogues that hybridize to complementary DNA and are highly sensitive and specific for recognizing single base pair mismatches.
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Schwarzenbach, H., Hoon, D. & Pantel, K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 11, 426–437 (2011). https://doi.org/10.1038/nrc3066
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