Fragment Length of Circulating Tumor DNA

Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring back...

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Bibliographic Details
Published in:PLoS genetics Vol. 12; no. 7; p. e1006162
Main Authors: Underhill, Hunter R., Kitzman, Jacob O., Hellwig, Sabine, Welker, Noah C., Daza, Riza, Baker, Daniel N., Gligorich, Keith M., Rostomily, Robert C., Bronner, Mary P., Shendure, Jay
Format: Journal Article
Language:English
Published: United States Public Library of Science 01.07.2016
Public Library of Science (PLoS)
Subjects:
Alleles
Animals
Biology and life sciences
Biomarkers, Tumor - blood
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Cell Line, Tumor
Deoxyribonucleic acid
DNA
DNA sequencing
DNA, Neoplasm - blood
DNA, Neoplasm - genetics
Experiments
Genes
Genetic aspects
Glioblastoma - blood
Glioblastoma - genetics
Hep G2 Cells
Humans
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Lung cancer
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Magnetic Resonance Imaging
Male
Medicine and Health Sciences
Melanoma
Melanoma - genetics
Melanoma - metabolism
Metastasis
Methods
Mutation
Neoplasm Transplantation
Proto-Oncogene Proteins B-raf - genetics
Rats
Research and Analysis Methods
Studies
Tumors
ISSN:1553-7404, 1553-7390, 1553-7404
Online Access:Get full text
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Summary:Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free DNA derived from healthy cells has proven challenging, particularly in non-metastatic solid tumors. In this study, distinct differences in fragment length size between ctDNAs and normal cell-free DNA are defined. Human ctDNA in rat plasma derived from human glioblastoma multiforme stem-like cells in the rat brain and human hepatocellular carcinoma in the rat flank were found to have a shorter principal fragment length than the background rat cell-free DNA (134-144 bp vs. 167 bp, respectively). Subsequently, a similar shift in the fragment length of ctDNA in humans with melanoma and lung cancer was identified compared to healthy controls. Comparison of fragment lengths from cell-free DNA between a melanoma patient and healthy controls found that the BRAF V600E mutant allele occurred more commonly at a shorter fragment length than the fragment length of the wild-type allele (132-145 bp vs. 165 bp, respectively). Moreover, size-selecting for shorter cell-free DNA fragment lengths substantially increased the EGFR T790M mutant allele frequency in human lung cancer. These findings provide compelling evidence that experimental or bioinformatic isolation of a specific subset of fragment lengths from cell-free DNA may improve detection of ctDNA.
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Conceived and designed the experiments: HRU JOK SH NCW KMG RCR MPB JS. Performed the experiments: HRU JOK SH NCW RD DNB KMG. Analyzed the data: HRU JOK SH NCW RD DNB KMG MPB RCR JS. Contributed reagents/materials/analysis tools: HRU JOK SH DNB KMG RCR MPB JS. Wrote the paper: HRU JOK SH NCW RD DNB KMG RCR MPB JS.
The authors have declared that no competing interests exist.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006162