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Searching For Cancer Maps In Free-Floating DNA

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Jay Shendure, a geneticist at the University of Washington. Dr. Shendure and his colleagues have taken important steps toward identifying the origins of cell-free DNA, which could have ramifications in finding clues about diseases.

“Loose pieces of DNA course through our veins. As cells in our body die, they cast off fragments of genes, some of which end up in the bloodstream, saliva and urine.

Cell-free DNA is like a message in a bottle, delivering secrets about what’s happening inside our bodies. Pregnant women, for example, carry cell-free DNA from their fetuses. A test that analyzes fetal DNAhas proved to be more accurate in screening for Down syndrome than standard blood tests.

In 2012, Jay Shendure, a geneticist at the University of Washington, and his colleagues were able to reconstruct the entire genome of a fetus from cell-free DNA in a pregnant woman’s saliva. A team of Stanford University researchers collected DNA fragments from the blood of patients who had received heart transplants and managed to find DNA from their donated hearts. (Tellingly, levels were highest in patients who were rejecting their hearts.)


These days, scientists are especially excited by the prospect of using cell-free DNA to test for cancer. Instead of relying on invasive biopsies, they hope to find blood-borne fragments that carry distinctive cancer mutations.

Unfortunately, the genetic sequence of a piece of cell-free DNA doesn’t tell researchers where in the body it originated — a valuable clue for doctors looking for diseases. “Knowing the origin of circulating DNA is of great importance,” said Alain R. Thierry, director of research at France’s National Institute of Health and Medical Research.

All the cells in our body typically descend from a single fertilized egg, and they inherit all the same genes. The reason we aren’t uniform sacs of protoplasm is that our cells turn those same genes on and off in distinctive patterns, thereby developing into different tissues. They’re like musicians at a piano recital: They sit at the same keyboard, but they play different songs.


But in a study published on Thursday in the journal Cell, Dr. Shendure and his colleagues took some important steps toward identifying the origins of free-floating DNA. To do so, they took advantage of a way that cells control their genes.” said

“DNA is wound around millions of protein clusters, resembling beads on a string. Some genes sit on stretches of DNA unencumbered by these clusters, called nucleosomes, but other genes are tucked deep inside them. By hiding genes, nucleosomes can silence them.

As it turns out, different types of cells squirrel away different stretches of DNA in nucleosomes. One of Dr. Shendure’s graduate students, Matthew W. Snyder, wondered what happened to those nucleosomes in dying cells.

A cell ending its useful life is shredded by enzymes. But nucleosomes, Mr. Snyder suggested, might shield the DNA they’ve hidden.


If so, then much of the cell-free DNA that scientists collect from blood samples should have come from nucleosomes. They could reveal the pattern of nucleosomes in the cells they came from — and thus tell researchers which kind of cell produced it.

Mr. Snyder and his colleagues put the idea to the test. They searched the blood of healthy individuals for cell-free DNA, and then searched a map of the human genome to figure out where each fragment came from. Much of the cell-free DNA came from regions in or around nucleosomes, just as Mr. Snyder had suggested.

The scientists then looked at the patterns of nucleosomes in different types of cells. They found that all the healthy subjects produced cell-free DNA that mainly came from nucleosomes found in blood cells.

But when they looked at cell-free DNA from people with advanced cancer, the picture was different.

In a patient with lung cancer, for example, the team found that the cell-free DNA fit a different pattern — one belonging to a type of lung cancer cell. The researchers went on to match cell-free DNA in other cancer patients to the types of cancer they had.


Dr. Thierry, who was not involved in the research, said the findings might eventually make it possible to use cell-free DNA to find important clues about diseases. Doctors might be able to use it to figure out the location of hard-to-find cancers, for example.

It could provide clues to diseases other than cancers as well. Free-floating genes shed by the heart, for example, might reveal damage from a heart attack. Cell-free DNA from neurons might signal a stroke.

William J. Greenleaf, a geneticist at Stanford, cautioned that the success of the new study owed much to the people Dr. Shendure and his colleagues had studied. It has long been known that people with advanced cancer shed a lot of cell-free DNA from their tumors. It may prove harder to trace the origin of cell-free DNA in people with other conditions.

Dr. Shendure agreed, calling his study a proof of concept — far from a test ready for the clinic.” said

“Obviously, there’s a lot of work from here to there,” he said.

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“Searching For Cancer Maps In Free-Floating DNA”