22 Jul Circulating Tumor DNA Size Enhances Liquid Biopsy Effectiveness
MedicalResearch.com Interview with:
Dr. Hunter R. Underhill MD, PhD
Department of Pediatrics, Division of Medical Genetics, Department of Radiology,
University of Utah, Salt Lake City, Utah
Department of Radiology and Department of Neurological Surgery
University of Washington
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: When cells undergo cell death (i.e., apoptosis) the DNA has the potential to enter the circulation. This DNA is not contained within a cellular membrane and is known as “cell-free DNA.” This is a naturally occurring process. The same process also occurs when malignant tumors grow and evolve. The deposition of cell-free DNA derived from tumors is known as “circulating tumor DNA.” Analysis of circulating tumor DNA holds the promise of detecting, diagnosing, and monitoring response to therapy of cancers through a simple blood draw – the “liquid biopsy.” The challenge has been isolation of circulating tumor DNA from the background of the naturally occurring cell-free DNA. This has been particularly difficult in non-metastatic solid tumors as circulating tumor DNA has been heretofore indistinguishable from normal cell-free DNA except for the occurrence of mutant alleles that commonly occur at a frequency below detection limits – the proverbial needle in a haystack.
Our study found a distinct size difference in DNA fragment length between circulating tumor DNA and cell-free DNA. Specifically, circulating tumor DNA is about 20-50 base pairs shorter than cell-free DNA originating from healthy cells. We were subsequently able to exploit this difference in size to enrich for circulating tumor DNA – essentially removing a large portion of the haystack that does not contain the needle to simplify the search.
MedicalResearch.com: What should readers take away from your report?
Response: The key message is that circulating tumor DNA has a distinct size compared to normal cell-free DNA. This difference gives us the opportunity to substantially improve the sensitivity of detecting circulating tumor DNA. As such, we are a step closer to broadening the clinical applications of the liquid biopsy.
Another notable message is that the biologic phenomenon driving the size difference remains unknown. We can only speculate as to the cause. Determining the etiology may prove valuable in our understanding and treatment of cancer.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: We studied circulating tumor DNA associated with glioblastoma multiforme and hepatocellular carcinoma in animal models of disease and then subsequently melanoma and lung cancer in human patients. Our human studies utilized a relatively small sample size. Future research would benefit from larger studies in humans across a broader variety of tumors to more fully describe the utility of fragment size selection for improving sensitivity of detecting circulating tumor DNA from non-metastatic solid tumors.
Technological developments for a more efficient approach to fragment size selection also merits consideration. Our use of polyacrylamide gel electrophoresis provided sufficient size resolution for isolation of specific fragment lengths, but this approach may not be a scalable methodology for handling large sample sizes associated with clinical applications.
MedicalResearch.com: Is there anything else you would like to add?
Response: Embedded within the paper is an advanced quantitative MRI technique for phenotyping tumors (e.g., differentiating bulky tumor growth vs. infiltrative tumor growth). Although the imaging technology was only applied in an animal tumor model, all images were acquired with a 3.0 T clinical scanner using a similar protocol previously applied in humans for studying white matter. As such, personalized medicine may be advanced through the future coupling of quantitative imaging with next-generation sequencing to more broadly and more specifically characterize individual tumors, monitor the individual response to therapy, identify tumor susceptibility to particular types of therapy, and collect and compare quantitative data (imaging and molecular) between patients.
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Fragment Length of Circulating Tumor DNA
Hunter R. Underhill ,Jacob O. Kitzman,Sabine Hellwig,Noah C. Welker,Riza Daza, Daniel N. Baker,Keith M. Gligorich,Robert C. Rostomily,Mary P. Bronner,Jay Shendure
PLOS Genetics Published: July 18, 2016
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