title: Fragment Length of Circulating Tumor DNA.
abstract: 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.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah, United States of America.|Department of Radiology, University of Utah, Salt Lake City, Utah, United States of America.|Department of Neurological Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Hunter R
authors.initials: HR
authors.lastname: Underhill
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.|Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jacob O
authors.initials: JO
authors.lastname: Kitzman
authors.affiliation: ARUP Laboratories, Salt Lake City, Utah, United States of America.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hellwig
authors.affiliation: ARUP Laboratories, Salt Lake City, Utah, United States of America.
authors.forename: Noah C
authors.initials: NC
authors.lastname: Welker
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Riza
authors.initials: R
authors.lastname: Daza
authors.affiliation: ARUP Laboratories, Salt Lake City, Utah, United States of America.
authors.forename: Daniel N
authors.identifier: 0000-0002-0513-6893
authors.initials: DN
authors.lastname: Baker
authors.affiliation: ARUP Laboratories, Salt Lake City, Utah, United States of America.|Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gligorich
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rostomily
authors.affiliation: ARUP Laboratories, Salt Lake City, Utah, United States of America.|Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Mary P
authors.identifier: 0000-0001-5574-4072
authors.initials: MP
authors.lastname: Bronner
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
mesh_terms: D000483:Alleles; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics*; D005909:Glioblastoma / Q000097:blood / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009368:Neoplasm Transplantation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051381:Rats
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf