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Clinical Laboratories and Pathology Groups

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University of Alberta researchers developed CIDER-Seq tool and protocols for the study, which they have made freely available to all scientists

Here’s another promising new technology which, given more research into effectiveness and safety, may soon lead to improved clinical laboratory cancer diagnostics. Oncology research scientists have focused much attention on understanding the role of extrachromosomal circular DNA (eccDNA) in human cancer. Now, a new gene sequencing method may help expand their knowledge about that and other circular DNA found in the genomes of bacteria, viruses, and other cells.

University of Alberta (UA) researchers have invented a new way for sequencing circular DNA, according to a recent study published in the journal Nature Protocols. As with any new technological method, this new tool—called CIDER-Seq—will need to be time-tested, but it does hold promise for providing valuable insights into the role these “mysterious loops” play not only in human disease, but in agricultural viruses as well.

A New Tool for Understanding DNA

DNA is considered “circular” when it has a closed loop with no ends. It differs from “linear” DNA chromosomes found in human cell nuclei. Circular DNA include:

Devang Mehta, PhD
Devang Mehta, PhD (above), Postdoctoral Fellow in the University of Alberta’s Department of Biological Sciences, and lead author of the UA study, describes the breakthrough in his team’s on-going work researching the role of eccDNA molecules. “We devised a new molecular biology method and a new bioinformatics algorithm to finally obtain full-length sequences of eccDNA,” he said in a news release. “Our method finally allows us to sequence these molecules completely and gives us and other researchers a tool to better understand what they actually do in the cell.” (Photo copyright: ecrLife.)

According to the UA study, circular DNA enrichment sequencing (CIDER-Seq) “is a technique to enrich and accurately sequence circular DNA without the need for polymerase chain reaction amplification, cloning, and computational sequence assembly.”

CIDER-Seq uses DNA sequencing technology from Pacific Biosciences, Inc. (PacBio) of Menlo Park, Calif. PacBio (NASDAQ:PACB) is an American biotechnology company founded in 2004 that develops and manufactures gene sequencing systems.

Understanding Circular DNA in Any Human or Plant Cell, Including Cancer

Because many viruses that infect crops have circular DNA, Mehta believes the new tool may be particularly helpful to agricultural scientists. His team of researchers, he noted in the UA news release, used an earlier version of CIDER-Seq to study crop plants in Kenya which were genetically engineered to resist circular DNA viruses.

“Our key advance is that, through our method, scientists can finally gain an unbiased, high-resolution understanding of circular DNA in any type of cell. With our invention of CIDER-Seq, we can start to begin to understand the function of these mysterious circular DNAs in human and plant cells,” Mehta said.

However, this technological advance may be equally welcomed by researchers investigating the role of eccDNA in human cancer. Though both healthy and diseased cells may contain circular DNA, the New York Times noted that the “mysterious loops” are “surprisingly common in cancer cells and play a bigger role in many types of cancers than was previously recognized.” The article goes on to state that until now there have not been effective methods for sequencing circular DNA.

In Clinical Chemistry, a panel of eccDNA experts discussed the critical role circular DNA plays in cancer, referred to as extrachromosomal DNA (ecDNA). “Importantly, in cancer cells, ecDNAs seem to be more transcriptionally active than their chromosomal counterparts and have been suspected to confer growth and survival advantage to cancer cells,” the article states.

According to the New York Times, scientists first discovered the existence of circular DNA in the 1960s when “little clumps of DNA” were detected alongside chromosomes. Today, researchers believe circular DNA is more common in the human genome than first realized and could be linked to a variety of conditions and diseases, not solely to cancer.

CIDER-Seq Research May Lead to New Clinical Laboratory Biomarkers

Birgitte Regenberg, PhD, Associate Professor in Ecology and Evolution at the University of Copenhagen, pioneered methods for detecting circular DNA. She told the New York Times, “I think we’re just opening our eyes up.”

Though she says the research has been “cancer-centered,” Regenberg maintains the role circular DNA plays in human biology may prove to be much broader.

“It’s like when a horse has blinders: The blinders focus the science, but they also prevent some things from being understood,” she said.

The University of Alberta news release states the CIDER-Seq data analysis software has been made available online for other scientists to use, along with step-by-step lab and computer protocols for analyzing the DNA sequences.

Clinical laboratory leaders should keep an eye on the use of CIDER-Seq technology. It may lead to the development of new biomarkers for cancer and other diseases.

—Andrea Downing Peck

Related Information:

Scientists Develop Tool to Sequence Circular DNA

Full-length Sequence of Circular DNA Viruses and Extrachromosomal Circular DNA Using CIDER-Seq

Scientists Are Just Beginning to Understand Mysterious DNA Circles Common in Cancer Cells

What is Extrachromosomal Circular DNA and What Does it Do?