Cancer biomarkers: Written in blood

Illustration by Oliver Munday

In 2012, Charles Swanton was forced to confront one of cancer's dirtiest tricks. When he and his team at the Cancer Research UK London Research Institute sequenced DNA from a handful of kidney tumours, they expected to find a lot of different mutations, but the breadth of genetic diversity within even a single tumour shocked them. Cells from one end differed from those at the other and only one-third of the mutations were shared throughout the whole mass. Secondary tumours that had spread and taken root elsewhere in the patients' bodies were different again1.

The results confirmed that the standard prognostic procedure for cancer, the tissue biopsy, is woefully inadequate like trying to gauge a nation's behaviour by surveying a single street. A biopsy could miss mutations just centimetres away that might radically change a person's chances for survival. And although biopsies can provide data about specific mutations that might make a tumour vulnerable to targeted therapies, that information is static and bound to become inaccurate as the cancer evolves.

Swanton and his team laid bare a diversity that seemed insurmountable. I am still quite depressed about it, if I'm honest, he says. And if we had higher-resolution assays, the complexity would be far worse.

But researchers have found ways to get a richer view of a patient's cancer, and even track it over time. When cancer cells rupture and die, they release their contents, including circulating tumour DNA (ctDNA): genome fragments that float freely through the bloodstream. Debris from normal cells is normally mopped up and destroyed by 'cleaning cells' such as macrophages, but tumours are so large and their cells multiply so quickly that the cleaners cannot cope completely.

By developing and refining techniques for measuring and sequencing tumour DNA in the bloodstream, scientists are turning vials of blood into 'liquid biopsies' portraits of a cancer that are much more comprehensive than the keyhole peeps that conventional biopsies provide. Taken over time, such blood samples would show clinicians whether treatments are working and whether tumours are evolving resistance.

As ever, there are caveats. Levels of ctDNA vary a lot from person to person and can be hard to detect, especially for small tumours in their early stages. And most studies so far have dealt with only handfuls or dozens of patients, with just a few types of cancer. Although the results are promising, they must be validated in larger studies before it will be clear whether ctDNA truly offers an accurate view and, more importantly, whether it can save or improve lives. Just monitoring your tumour isn't good enough, says Luis Diaz, an oncologist at Johns Hopkins University in Baltimore, Maryland. The challenge that we face is finding true utility.

If researchers can clear those hurdles, liquid biopsies could help clinicians to make better choices for treatment and to adjust those decisions as conditions change, says Victor Velculescu, a genetic oncologist at Johns Hopkins. Moreover, the work might provide new therapeutic targets. It will help bring personalized medicine to reality, says Velculescu. It's a game-changer.

Scientists first reported finding DNA circulating in human blood in 1948 (ref. 2), and specifically in the blood of people with cancer in 1977 (ref. 3). It took another 17 years to show that this DNA bore mutations that are hallmarks of cancer proof that it originated from the tumours4, 5.

The first practical use of circulating DNA came in another field. Dennis Lo, a chemical pathologist now at the Chinese University of Hong Kong, reasoned that if tumours could flood the blood with DNA, surely fetuses could, too. In 1997, he successfully showed that pregnant women carrying male babies had fetal Y chromosomes in their blood6. That discovery allowed doctors to check a baby's sex early in gestation without disturbing the fetus, and ultimately to screen for developmental disorders such as Down's syndrome without resorting to invasive testing. It has revolutionized the field of prenatal diagnostics (see Nature 507, 19; 2014).

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Cancer biomarkers: Written in blood