Genetic Analysis of DNA Excreted in Urine: A New Approach for Detecting Specific Genomic DNA Sequences from Cells Dying in an Organism

Ботезату, И. В.; Serdyuk, O. I.; Потапова, Г. И.; Шелепов, В. П.; Alechina, R.P.; Molyaka, Yuriy; Ананьев, В. С.; Bazin, I.; Garin, A.; Narimanov, Mehti; Кныш, В И; Melkonyan, Hovsep; Umansky, Samuil R.; Lichtenstein, A. V.

doi:10.1093/clinchem/46.8.1078

Cited by 318 publications

(219 citation statements)

References 20 publications

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“…Low cfDNA quantities are mainly caused by fast DNA clearance via filtering by the liver and kidney. 90,91 The average cfDNA half-lifetime of fetal DNA in the maternal circulation is only 16.3 minutes, 31 whereas the half-lifetime of ctDNA is reportedly higher in blood (up to 2 hours 43 ) and urine (up to 5 hours 92 ). These fast turnover rates can -in theory-facilitate real-time assessment of genomic aberrations.…”

Section: Et Hod S To Ac Cu Ra Te L Y M E Asu R E Th E Qu a N Ti Tmentioning

confidence: 99%

A field guide for cancer diagnostics using cell‐free DNA: From principles to practice and clinical applications

Volckmar

Sültmann

Riediger

et al. 2017

Genes Chromosomes & Cancer

162

151

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Recently, many genome-wide profiling studies provided insights into the molecular make-up of major cancer types. The deeper understanding of these genetic alterations and their functional consequences led to the discovery of novel therapeutic opportunities improving clinical management of cancer patients. While tissue-based molecular patient stratification is the gold standard for precision medicine, it has certain limitations: Tissue biopsies are invasive sampling procedures carrying the risk of complications and may not represent the entire tumor due to underlying genetic heterogeneity. In this context, complementary characterization of genetic information in the blood of cancer patients can serve as minimal-invasive 'liquid biopsy'. Fragments of circulating cell-free DNA (cfDNA) are released from tissues of healthy individuals as well as cancer patients. The fraction of cfDNA that is released from primary tumors or metastases (i.e. circulating tumor DNA, ctDNA) represents genetic aberrations in cancer cells, which are a potential source for diagnostic, prognostic, and predictive biomarkers. Recent studies have demonstrated technical feasibility and clinical applications including detection of drug targets and resistance mutations as well as longitudinal monitoring of tumors under therapy. To this end, a variety of pre-analytical procedures for blood processing, isolation and quantification of cfDNA are being employed and several analytical methods and technologies ranging from PCR-based single locus assays to genome-wide approaches are available, which considerably differ in sensitivity, specificity, and throughput. However, broad implementation of ctDNA analysis in daily clinical practice requires a thorough understanding of theoretical, technical, and biological concepts and necessitates standardization and validation of pre-analytical and analytical procedures across different technologies. Here, we review the pertinent literature and discuss the advantages and limitations of available methodologies and their potential applications in molecular diagnostics.

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Section: Et Hod S To Ac Cu Ra Te L Y M E Asu R E Th E Qu a N Ti Tmentioning

confidence: 99%

A field guide for cancer diagnostics using cell‐free DNA: From principles to practice and clinical applications

Volckmar

Sültmann

Riediger

et al. 2017

Genes Chromosomes & Cancer

162

151

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“…Nucleosomes are present not only in the blood of SLE patients (79) but also in the blood of healthy individuals, who excrete nucleosome-sized DNA in urine (80,81). Thus, nucleosomes are poorly immunogenic in normal conditions.…”

Section: Systemic Lupus Erythematosus or The Disadvantages Of Apoptosismentioning

confidence: 99%

High‐mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity

Bianchi¹,

Manfredi²

2007

Immunological Reviews

526

447

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Tissue damage occurs often in the life of mammals and is usually repaired. Dying cells are swiftly phagocytosed, but before disappearing, they alert surrounding cells to activate homeostatic programs. They release signals that recruit inflammatory cells to the site of injury, promote cell migration and cell division to replace dead cells, and activate the immune system in anticipation of microbial invasion. Many of these events involve high-mobility group box 1 protein (HMGB1), a nuclear protein that is released passively when necrotic cells lose the integrity of their membranes. HMGB1 behaves as a trigger of inflammation, attracting inflammatory cells, and of tissue repair, recruiting stem cells and promoting their proliferation. Moreover, HMGB1 activates dendritic cells (DCs) and promotes their functional maturation and their response to lymph node chemokines. Activated leukocytes actively secrete HMGB1 in the microenvironment. Thus, HMGB1 acts in an autocrine/paracrine fashion and sustains long-term repair and defense programs. DCs secrete HMGB1 several hours after contact with the first maturation stimulus; HMGB1 secretion is critical for their ability to reach the lymph nodes, to sustain the proliferation of antigen-specific T cells, to prevent their activation-dependent apoptosis, and to promote their polarization towards a T-helper 1 phenotype. These immune responses will also be directed against self-antigens that DCs process at the time of injury and can lead to autoimmunity.

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“…The half-life of cfDNA in the circulation is estimated to be between 16 min and 2.5 h [15,16]. cfDNA is eliminated from the circulation by nuclease activity [16,17], by uptake in the liver and spleen with subsequent degradation by macrophages [18] and by renal excretion [19][20][21] (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Cell‐free tumour DNA testing for early detection of cancer – a potential future tool

et al. 2019

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In recent years, detection of cell‐free tumour DNA (ctDNA) or liquid biopsy has emerged as an attractive noninvasive methodology to detect cancer‐specific genetic aberrations in plasma, and numerous studies have reported on the feasibility of ctDNA in advanced cancer. In particular, ctDNA assays can capture a more ‘global’ portrait of tumour heterogeneity, monitor therapy response, and lead to early detection of resistance mutations. More recently, ctDNA analysis has also been proposed as a promising future tool for detection of early cancer and/or cancer screening. As the average proportion of mutated DNA in plasma is very low (0.4% even in advanced cancer), exceedingly sensitive techniques need to be developed. In addition, as tumours are genetically heterogeneous, any screening test needs to assay multiple genetic targets in order to increase the chances of detection. Further research on the genetic progression from normal to cancer cells and their release of ctDNA is imperative in order to avoid overtreating benign/indolent lesions, causing more harm than good by early diagnosis. More knowledge on the sources and elimination of cell‐free DNA will enable better interpretation in older individuals and those with comorbidities. In addition, as white blood cells are the major source of cell‐free DNA in plasma, it is important to distinguish acquired mutations in leukocytes (benign clonal haematopoiesis) from an upcoming haematological malignancy or other cancer. In conclusion, although many studies report encouraging results, further technical development and larger studies are warranted before applying ctDNA analysis for early cancer detection in the clinic.

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Genetic Analysis of DNA Excreted in Urine: A New Approach for Detecting Specific Genomic DNA Sequences from Cells Dying in an Organism

Cited by 318 publications

References 20 publications

A field guide for cancer diagnostics using cell‐free DNA: From principles to practice and clinical applications

A field guide for cancer diagnostics using cell‐free DNA: From principles to practice and clinical applications

High‐mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity

Cell‐free tumour DNA testing for early detection of cancer – a potential future tool

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