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 2016-07, Vol.12 (7), p.e1006162-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: Article
Language:English
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
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Description
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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006162