Rapid sequencing could spot chromosal abnormalities and so help to detect tumours. Credit: LIFE TECHNOLOGIES AND DIGIZYME, INC

By looking for the genetic alterations that occur in tumour cells, a new assay could allow clinicians to use a simple blood test to track cancer during and after treatment.

The technique, developed by Victor Velculescu and Rebecca Leary at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, and their colleagues, generates patient-specific biomarkers using high-throughput DNA sequencing1. So far it has only been tested in a proof-of-concept study using six tumours, and there are logistical hurdles to overcome before it could see widespread use. But researchers see the technique, reported today in Science Translational Medicine, as a sign of things to come.

"I am optimistic," says Joe Gray, a cancer researcher at the Lawrence Berkeley National Laboratory in California. "It does seem to be an exciting step in the direction of truly personalized medicine."

A tumour's trail

In tumour cells, the normal means of repairing DNA breaks down. As a result, the genetic landscape of a cancer cell differs from that of the patient's genome, with entire segments of DNA exchanged both within and between chromosomes.

In some cancers of blood or of immune cells there are characteristic rearrangements that can be used to monitor the disease. But it has been difficult to design tests for solid tumours, says Felix Mitelman, a cancer researcher at Lund University in Sweden. It is technically challenging to isolate intact chromosomes from these tumours, he says, and the exact location and kind of rearrangements vary from person to person.

The ability to detect chromosomal aberrations in all cancers would be a "revolution" in cancer diagnostics, he adds.

It does seem to be an exciting step in the direction of truly personalized medicine. Joe Gray , Lawrence Berkeley National Laboratory

To do this, Velculescu and his colleagues generated about 40 million high-quality sequencing reads from each of four colorectal cancers and two breast cancers. By comparing these reads to a reference human genome sequence, they were able to find multiple regions that had been shuffled in each cancer.

The team then used this information to develop a test that would specifically target the rearranged regions. Tumours shed DNA into the bloodstream, and because the biomarker-development technique uses the polymerase chain reaction to amplify even minute quantities of DNA — it could theoretically be used to detect even tiny tumours, Leary says.

To see if this was the case, the team used their test to track the progression of a colon cancer before and after surgery to remove the tumour. They found that 127 days post-surgery, the amount of tumour DNA had dropped substantially, but did not disappear. This was consistent with the finding that some cancer cells still lurked in the patient's liver.

Is the price right?

Leary and her colleagues were able to find multiple rearrangements in each tumour without resorting to full-genome sequencing. Nevertheless, the team estimates that the cost of sequencing is currently about US$5,000 per sample, with another$500 for data analysis and the design and testing of the biomarker.

That may be prohibitively expensive now, says Leary, but sequencing costs are plummeting. In contrast, computed tomography imaging can cost \$1,500 per scan, she notes, whereas the biomarkers her team developed will only be expensive during the initial design phase — subsequent testing using the same markers should be much cheaper.

And yet the most difficult aspect of the work may not be the sequencing, but rather the design and testing of the biomarkers. Each customized biomarker would have to be thoroughly validated before it could be used, says Arul Chinnaiyan, a cancer researcher at the University of Michigan in Ann Arbor. "Right now we are certainly far from being able to handle the cost and the logistics of personalizing it this much," he says. "It would be a mini research project for each patient."