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Even in the earliest stages of disease, tumours give their presence away by releasing genetic clues into the bloodstream. We are starting to decipher them

Written in blood?

Science Photo Library

CASEY LIM (not her real name) was 11 weeks pregnant when she gave a blood sample to test for Down’s syndrome. It revealed multiple abnormalities in fragments of DNA circulating in her blood. Further analysis showed that the mutant DNA wasn’t from the fetus but from Lim’s own white blood cells. A form of blood cancer called follicular lymphoma, which she had battled two-and-a-half years earlier, had stealthily returned.

Lim was one of the lucky ones. All too often, cancers are caught only after they have spread and mutated into subtly different forms. This ability to evolve and resist our best treatments is what makes cancer such a formidable foe. One way to root out its weaknesses is to repeatedly remove chunks of tumour for analysis, but that is invasive and often risky.

So how do we keep an eye on a cancer’s ominous transformations, figure out the best way to treat it and check that it is not stealthily growing back? The answer could be written in blood. A test based on tiny bits of DNA released into the circulation by cancer cells might even give doctors a way to catch the disease earlier.

“The best time to treat cancers is when there are very few cancer cells, when there are fewer chances for them to develop resistance,” says Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University in Baltimore, Maryland.

Vogelstein’s lab is one of several dedicated to developing a blood test to spot cancer early and follow its every move. It’s a laudable ambition. To make these “liquid biopsies” reliable enough to be useful, however, they will have to figure out how to track down and decode the faint, potentially misleading traces tumours leave in the blood.

All cells, including cancer cells, release DNA into the blood when they die. Researchers have known for some time that it is possible to detect this free-floating DNA in the circulation, and that people with cancer have more of it than healthy people. In the earliest stages of the disease, the number of fragments deriving from cancer cells – known as circulating tumour DNA, or ctDNA – is vanishingly small. But as the tumour grows, so does the quantity of DNA fragments.

In the late 1990s, Dennis Lo, now at the Chinese University of Hong Kong, was struck by the opportunities this offered. His main interest was in developing non-invasive ways to detect fetal abnormalities. Eventually, he came up with a way to detect fetal DNA in the blood plasma of the mother, and within 10 years he’d devised a blood test for Down’s syndrome. He also set his sights on cancer.

Tumour DNA is rarer than fetal DNA, but as sequencing technology has improved, so has our ability to catch it and read what it can tell us about the cancer. The simplest strategy is to search for genetic mutations you already know about from a biopsy of the tumour.

In 2007, Vogelstein’s group used this approach to monitor tumours in 18 people with bowel cancer. Their technique took advantage of the fact that bits of single-stranded DNA stick to other bits with the corresponding sequence of nucleotides. Once they had generated multiple copies of all the DNA fragments in the blood samples, using a process called PCR, they added tiny magnetic beads covered with many copies of a sequence mirroring the target mutation. Any bits of mutant DNA that fastened to these beads were then pulled out and counted, giving an estimate of its concentration in the blood.

After these patients had their tumours removed surgically, a blood test was still able to detect ctDNA in most of them, even though quantities had fallen dramatically – and all of those people eventually saw their cancer return. In the handful of patients with no detectable tumour DNA in their blood, the cancer has not come back. This suggests that the quantity of ctDNA in blood reflects tumour size, and that liquid biopsies could be a useful monitoring tool.

Since then, Vogelstein has shown that almost every type of cancer sheds fragments of DNA into the blood. In 2014, his group announced the detection of ctDNA in the blood of more than 75 per cent of a group of 640 people with a range of cancers, such as advanced pancreatic, ovarian, colorectal and breast cancer. Brain, renal and prostate cancer seemed to shed fewer DNA fragments – although they could still be detected in half of those whose disease was at an advanced stage (Science Translational Medicine, vol 6, p 224).

Shards of DNA can also be used to predict whether those with cancer will respond to drugs. Last year, for instance, the European Medicines Agency approved a blood test that indicates whether people with non-small-cell lung cancer will respond to gefitinib, a drug which works against cells carrying a particular mutation. This is a big deal because taking a lung biopsy is difficult, meaning doctors often don’t get enough tissue to understand the tumour. “That’s a perfect situation for a liquid biopsy,” says Vogelstein.

You also want to look at how the cancer evolves to evade treatment. One of cancer’s grim ironies is that the better the drug you throw at it, the more you prime it to resist. “Some of the targeted drugs against cancer are so dramatically effective that they select for major changes in the cancer biology,” says Daniel Haber, director of the Massachusetts General Hospital Cancer Center in Boston. “This is a great rationale for monitoring cancers through the blood continuously.”

Vanishingly rare

At the Institute for Cancer Research in London, Delila Tandefelt and her colleagues have done just this, taking monthly blood samples from men with advanced prostate cancer. Their aim was to look for changes in a known genetic sequence that predict how likely it is that the patient will respond to the drug abiraterone. Sure enough, the researchers spotted the emergence of resistance to the drug four months earlier than with standard clinical assessments, such as CT scans. “Instead of giving them abiraterone, which they probably won’t benefit from, we can give them an alternative treatment,” says Tandefelt.

Impressive as these early applications of liquid biopsies are, they are merely the low-hanging fruit. “A major interest all along has been to develop a diagnostic test that could be applied to asymptomatic people,” says Vogelstein. Considering that even in wealthy countries nearly half of cancers are diagnosed at a late stage, a blood test that could detect the disease early could save millions of lives.

The devil is in deciding what to look for. If you already have a sample of the cancer tissue, it’s relatively easy to probe the blood for its signature mutations. If not, you need to look for all kinds of mutations. What’s more, ctDNA is exceedingly rare in the early stages of cancer. “The problem with blood is there’s a lot of stuff in it, and the material from cancer is relatively small,” says Haber.

Tumours release all kinds of signals into the bloodstream

Steve Gschmeissner/SPL/Getty

Another approach is to sequence all of the circulating DNA in the blood and then look for differences in the ratios of fragments from various regions of chromosomes, the thread-like structures in cells that contain most of your DNA. This might flag up whether some areas have become duplicated, deleted or rearranged – all classic hallmarks of cancer.

In 2012, Vogelstein’s group sequenced DNA from the blood of 10 people with late-stage breast or colorectal cancer and 10 healthy people, searching for these structural alterations. They detected abnormalities in all of the cancer patients, but none of the healthy people. However, it is not certain that the technique would work in cancer’s early stages, when there are fewer bits of rogue DNA to analyse. Nor do we know if it would detect every significant alteration, or distinguish between pernicious and harmless changes.

The caveats don’t end there. Even a test that is sensitive and broad enough to detect very early cancers runs the risk of generating false positives (see “When is a cancer not a cancer?“) unless you can confirm the result with some sort of imaging technique.

And assuming you can detect the genetic signature of a cancer, how would you know which part of the body is affected? Some mutations provide a clue: a mutant KRAS gene, for instance, is usually associated with lung, colon or pancreatic cancer. Other mutations, such as in the p53 gene, could be associated with just about any form of the disease.

The good news is that ctDNA isn’t the only tumour-derived material in the blood. There are also circulating tumour cells. They are harder to spot than ctDNA as there is typically just one CTC for every billion blood cells, and they may not get into the bloodstream until later in the cancer’s development. It is possible to catch them, though, either by separating them by size from smaller white blood cells or fishing them out using magnetically tagged antibodies that latch onto specific cell-surface markers. And CTCs can reveal far more than ctDNA.

With CTCs you can scrutinise not only the tumour’s DNA but also its RNA – the chemical go-between that helps translate genetic code into proteins. This extra information ups the chances of pinpointing the site of the cancer and offer clues about the genetic reshuffling that might be driving it, such as translocations – where a chunk of DNA has jumped to a different location in the chromosome, potentially altering the expression of genes nearby. Such insights could be vital in diagnosing prostate cancer, for example, which is more often characterised by translocations than a particular mutation.

Another option is to focus on platelets, the sticky discs in blood which promote wound healing by forming clots. As they circulate, platelets accumulate fragments of RNA from the tissues they come into contact with, including cancer cells. By sequencing this RNA, you can learn about tumours in their earliest incarnations, long before CTCs can be detected. Indeed, Thomas Wurdinger at the VU University Medical Center in Amsterdam, and his colleagues recently used platelet RNA to distinguish cancer patients from healthy people with 96 per cent accuracy. They were also able identify the location of the primary tumour in 71 per cent of cases.

Then there are exosomes, tiny secreted packages containing DNA, RNA and proteins. Last year, researchers at the University of Texas MD Cancer Center in Houston were able to differentiate people with pancreatic cancer from healthy people by searching the blood for exosomes carrying a particular protein.

So ctDNA is not the only game in town. It remains a strong contender, though, and methods for reading abnormal DNA fragments are improving all the time. Lo’s group, for instance, has developed a novel technique that looks at methylation – where chemical tags known as methyl groups stick to DNA, often altering gene expression. This allows them to trace ctDNA back to its tissue of origin by comparing its methylation pattern against a database of tissue types.

Casey Lim’s cancer was spotted because she gave a blood sample to Lo, who was testing this new approach. It traced the abnormal DNA to her immune cells. “Chemotherapy had to be commenced immediately,” says Lo. “Given the early stage of pregnancy, the patient opted for a termination, received the chemotherapy and is currently well.”

Lo and his colleagues also recently discovered that DNA fragments from tumours tend to be significantly shorter or longer, on average, than those from healthy cells. They showed that the mere presence of these short or long fragments is enough to distinguish people with liver cancer from healthy people, even at a very early stage of the disease.

As the sensitivity of such tests improves, they could start to make a real difference. Vogelstein points out that on average it takes 20 to 30 years for a cancer to progress from initial mutations to a full-blown metastatic disease. That is a big window in which to intervene, one that we are failing to exploit.

“In the US this year there will be about 55,000 people who die from colorectal cancer, and every one of them will only have died because their cancers were not detected in the first 27 years or so,” says Vogelstein. So even if they can’t reliably detect cancer in its earliest stages, blood-based biopsies could still give us a valuable head start.


Zeph 3:17 Jehovah your God is in the midst of you. As a mighty One, he will save. He will exult over you with rejoicing. He will become silent in his love. He will be joyful over you with happy cries....... Love it....a beautiful word picture.

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The problem is they need to be looking for it ... each test costs money so they say, so when you go for a blood test they do the bare necessities unless there is a reason to go further. Why do a blood biopsy unless a patient is showing symptons in other ways?  They certainly won't do one for every patient needing a routine blood test. 

<p>"Jehovah chooses to either 'reveal' or 'conceal' - cherish what he reveals and be patient with what he conceals."

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