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Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

5507073256_36387f3df9_zBlood is a remarkable liquid. Not only does it carry red blood cells to deliver oxygen, it also transports cells of the immune system to protect us from infection. But there's another, hidden payload: bits of genetic material derived from dying cells throughout the body. In a patient with cancer, a tiny fraction of this circulating DNA comes from tumor cells.

Now researchers in the laboratories of Stanford radiation oncologist Maximilian Diehn, MD, PhD, and hematologist and oncologist Ash Alizadeh, MD, PhD, have found a way to read these genetic messages and use them to diagnose lung tumors and monitor how they respond (or don't) to treatment. The technique is highly sensitive and should be broadly applicable to many types of solid tumors. It also bypasses some of the more fussy patient-optimization steps that have previously been required.

From our release:

“We set out to develop a method that overcomes two major hurdles in the circulating tumor DNA field,” said [Diehn]. “First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it’s necessary to have a test that works off the shelf for the majority of patients with a given cancer.”


“We’re trying to develop a general method to detect and measure disease burden,” said Alizadeh, a hematologist and oncologist. “Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we’re in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily.”

Using their technique, the researchers were able to identify 50 percent of patients with Stage I cancers, and all patients with more advanced disease. The research was published Sunday in Nature Medicine.

The approach, which the researchers have dubbed CAPP-Seq, relies on a combination bioinformatics and deep sequencing of regions of the genome shown in national databases to be mutation hotspots. Again, from our release:

Tumor DNA differs from normal DNA by virtue of mutations in the nucleotide sequence. Some of the mutations are thought to be cancer drivers, responsible for initiating the uncontrolled cell growth that is the hallmark of the disease. Others accumulate randomly during repeated cell division. These secondary mutations can sometimes confer resistance to therapy; even a few tumor cells with these types of mutations can expand rapidly in the face of seemingly successful treatment.

“Cancer is a genetic disease,” Alizadeh said. “But unlike Down syndrome, for example, which has a single dominant cause, for most cancers it’s very difficult to identify any one particular genetic aberration or mutation that is found in every patient. Instead, each cancer tends to be genetically different from patient to patient, although sets of mutations can be shared among patients with a given cancer.”

By identifying several mutations in each patient, and searching for those sequences in their blood, the researchers can home in specifically on tumor DNA. Using the technique, they showed that levels of tumor DNA correlate with tumor volume in the patient. Tumor DNA also shows prognostic promise. One patient presumed to be free of disease after treatment, but who still had circulating tumor DNA, suffered a disease recurrence and eventually died of the cancer. Another in whom traditional imaging showed a mass remaining after treatment, but who had no evidence of circulating tumor DNA, remained disease free during the study (the mass was likely scar tissue caused by treatment).

The researchers are now working to design clinical trials to assess whether CAPP-Seq can affect patient outcomes and to apply it to more types of solid cancers.

Previously: Researchers use ultrafast microscopic camera to detect cancer cells in the bloodstream, What's in YOUR blood? A simple blood test may change the face of prenatal care and Developing a mini microscope that could help researchers detect the seeds of cancer earlier
Photo by Rosmary

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