DNA sequencing from peripheral blood test detects cancer

Atypical changes in chromosomal DNA drives the development and progression of cancer. There are a variety of modifications that promote cancer. These include abnormal chromosome numbers, rearrangements of chromosomes, gene duplications, and point mutations. The ability to identify these abnormalities in cancer patients is central to disease diagnosis, staging, and treatment. The current methods that are used clinically to identify chromosomal changes rely on analyses of tissue from tumor biopsies. While biopsy samples provide a wealth of information about abnormalities in tumors, they often require invasive procedures which may be prone to sampling error. The ability to detect chromosomal changes that cause cancer in peripheral blood (blood in systemic circulation) samples may allow earlier, and more accurate diagnosis.

In a recent study in Science Translational Medicine, researchers at Johns Hopkins  show that it is possible to get detailed information about the characteristics of a tumor’s chromosomal DNA from peripheral blood samples. The authors exploit the fact that dead or dying tumor cells frequently dump their contents into the bloodstream. A major component of these intracellular contents is the chromosomal DNA that contains the harmful modifications that drive tumor growth.

The authors isolated this circulating cell-free DNA (CFDNA) from both cancer patients (colon and breast cancer, specifically) and healthy volunteers and used whole genome sequencing (WGS) to assess for chromosomal abnormalities.

The authors saw chromosomal abnormalities such as, chromosomal copy number changes and genomic rearrangements, in the CFDNA specifically from cancer patients and not from healthy volunteers. Interestingly, the chromosomal abnormalities the authors detected corresponded to common mutations seen in these types of cancers. Previous studies have shown that it is possible to observe cancerous changes in chromosomal DNA from the peripheral blood of cancer patients. These methods, however, required prior knowledge of what chromosomal changes might be present—that is, the investigators needed to know ahead of time what to specifically look for. The current study demonstrates that it is possible to measure chromosomal changes in tumors using blood samples without advanced knowledge of the mutations that caused the cancer. This opens up the possibility of being able to fully characterize the unique defects in a patient’s tumor and allowing for individual tailoring of therapy. The authors also compare chromosome alterations from colorectal cancer cell lines (cells capable of growing in culture) and xenografts (cells or tissues from one species grown in a different species) to the blood from the colon cancer patients.  They found that they both showed a ≥5 chromosomal modifications compared to healthy volunteers (less than 2.4 modifications).

Although this technology is promising, substantial obstacles must be overcome before WGS on peripheral blood becomes a widely-used clinical technique.  First, the ability of WGS to work properly depends on the amount of mutant CFDNA obtained for sequencing. Chromosomal abnormalities that are present in small amounts may be missed (i.e. small tumors). Of note, the patients analyzed in this study all had advanced disease. Further investigations into whether this technique can identify chromosomal abnormalities during early stage disease or in instances of diagnostic uncertainty are warranted. Second, it is not clear to what extent the chromosomal abnormalities detected in peripheral blood represent the DNA defects in actual tumors. Are there additional mutations contained in tumor tissues that do not show up in the blood? Further study is necessary comparing peripheral blood sequencing analyses to those performed on biopsy samples obtained from the same patient. This will be especially important for applications which seek to use the information garnered from WGS of peripheral blood to guide treatment decisions. Finally, the sequencing techniques used in this study are expensive and preclude routine clinical use at this time. Although, based on the current trend of rapidly deceasing costs associated with high-throughput DNA sequencing technologies it is plausible that clinical testing of this sort will become affordable in the near future.

Research like this highlights the importance of donating blood samples so that scientists can accelerate cancer detection methods, diagnosis and treatments.

Jemima Escamilla is a senior Ph.D candidate in Molecular and Medical Pharmacology at the UCLA David Geffen School of Medicine. Her research focus integrates hormonally regulated cancer progression and cancer immunology.