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A Personalized Tumor Tracker

DNA changes could help doctors see if stray cancer cells remain after treatment.
February 18, 2010

Tracking tiny amounts of a patient’s unique cancer DNA could provide a new way of detecting small tumors or stray cancer cells that linger after treatment. Researchers from Johns Hopkins University and Life Technologies Corporation, a biotechnology tools company, used fast and cheap sequencing methods to spot genetic alterations in breast and bowel cancers in individual patients. Once found, the researchers used stretches of rearranged DNA to construct personalized biomarkers that allow them to detect even faint traces of tumor DNA.

Tracking cancer: Victor Velculescu (shown here), a physician and researcher at Johns Hopkins University, has developed a new way to use DNA sequencing to track the subtle signs of cancer that may linger after treatment.

As our understanding of cancer grows, scientists are beginning to view it as a chronic disease that is very difficult to eliminate entirely. Technologies like this one could provide ways to track it and keep it in check. The technique exploits a well-known tendency of tumors to sport scrambled chromosomes. Such swapping around of big chunks of DNA may in fact be one of the key events contributing to cells becoming cancerous in the first place.

Existing biomarkers are mostly protein-based and available for only some types of cancers. An example is the PSA protein that indicates prostate cancer. But because these proteins aren’t always unique to cancer cells, they aren’t very sensitive. “Our genetic markers work because they are extremely different” from the DNA in healthy cells, says Victor Velculescu, who led the research. “We could easily find one piece of cancer DNA among 400,000 normal ones.” The research was published today in the journal Science Translational Medicine.

While scientists have long known that cancer cells tend to harbor scrambled DNA, using this information to track the progression of cancer, or the effectiveness of treatment, has been a challenge. That’s because the precise nature of the genetic change is different in each patient, making these markers hard to find. The notable exceptions are several types of blood cancers that always display the same type of DNA rearrangement.

To tackle solid tumors with unpredictable genetic changes, Velculescu’s team turned to new sequencing technologies that have brought sequencing costs down tremendously over the past few years. Cheap sequencing meant the scientists could search the entire genome for signs of cancer. They used technology from Applied Biosystems, part of Life Technologies, to sequence the genomes of four bowel and two breast cancer genomes along with the genomes of four patients’ healthy tissue.

Applied Biosystems approach works by chopping the genome up into 200 million pieces that are each about 1,500 DNA base pairs long, and then sequencing just the 25 base pairs at the edges of these pieces, yielding pairs of mated tags. By comparing the sequences of these DNA ends against a healthy reference genome as well as between the patients’ normal and tumor genomes, the researchers could spot rearrangements between chunks of DNA. Velculescu’s team found about nine regions of swapped DNA in each tumor, providing unique biomarkers for each patient’s tumors.

The researchers then tracked the level of abnormal DNA as one of the colon cancer patients underwent different types of treatment. After surgery, chemotherapy, and surgical removal of metastases from the liver, the level of cancer-specific DNA in his blood dropped from 37 percent to 0.3 percent. This showed that some cancer cells still remained in the liver, indicating a need to remain vigilant and consider further treatment.

The research is an “exciting step down the road toward personalized cancer medicine,” says Peter Johnson at the University of Southampton and Cancer Research UK’s chief clinician. “The detection of DNA changes, unique to individual cancers, has proved to be a powerful tool in guiding the treatment of leukemia. If this can be done for other types of cancer like bowel, breast, and prostate, it will help us to bring new treatments to patients better and faster than ever.”

Velculescu says the biggest caveat to a wide clinical use of the technique is the cost. While the price of sequencing has dropped dramatically, the analysis costs around $5,000 per genome. In an editorial accompanying the paper, Ludmila Prokunina-Olsson and Stephen Chanock of the National Cancer Institute, in Bethesda, MD, point out that researchers will need to sequence a number of cancer genomes before the approach can be put into clinical practice. For example, scientists need to assess how reliably these DNA rearrangements can be detected, whether certain types of rearrangements are most useful in tracking cancer, and whether certain parts of the genome tend to harbor these changes. In addition, researchers need to show that detecting latent cancer DNA can help tailor treatment, improving a patient’s long-term health.

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