08 July 2019

Many advanced colon cancers were 'born' ready to spread

Genetic analysis of tumour samples in patients with advanced colon cancer revealed that spreading likely occurred very early – before the cancer was even diagnosed.

In most patients with metastatic colon cancer, the disease may have begun spreading throughout the body very early on – when the original tumour was no bigger than a poppy seed, a new study suggests.

Metastatic refers to the most advanced stage of cancer, when the original tumour has spread to distant sites in the body.

Early metastases

Traditionally, that's been seen as a "late" event – the result of a cancer accumulating many mutations that allow it to invade various tissues in the body, said Christina Curtis, lead researcher on the new study.

Her team's findings turn that viewpoint on its head.

Through genetic analysis of tumour samples, researchers traced the origins of metastases in 21 patients with advanced colon cancer. They found that for 80%, those metastases likely occurred very early – before the cancer was even diagnosed.

Essentially, that means some cancers are "born to be bad", said Curtis, an assistant professor of medicine and genetics at Stanford University in California.

While that might sound demoralising, she said the results can actually be viewed in a positive light.

One day, Curtis explained, doctors might be able to use tumours' genetic characteristics to figure out which patients with early-stage colon cancer need more aggressive treatment.

Discovering genetic 'drivers'

That could mean, for example, giving chemotherapy after surgeons have removed the colon tumour – to try to wipe out tumour cells that have travelled to other sites in the body.

Plus, Curtis said, discovering which genetic "drivers" cause cancer to spread early could allow researchers to develop new drugs that target those mechanisms.

According to Dr Martin Weiser, a colon cancer specialist at Memorial Sloan Kettering Cancer Center in New York City, "These findings are very important. This is top-notch work."

Many researchers and doctors have suspected metastases often get their start early on, he noted, but this is actual proof from patient tumour samples.

"This is showing there are molecular changes that happen early," Weiser said. That early occurrence, he added, should make it easier to pinpoint the particular genetic culprits.

"Maybe we can figure out which patients need additional treatment early on, and which ones don't," Weiser said.

Combination of gene mutations

For the study, published in Nature Genetics, Curtis and her colleagues started with tumour samples from 21 patients with colon cancer that had spread to the liver or the brain.

For each patient, the researchers compared the pattern of genetic mutations in the original colon tumour with that in the metastases.

The investigators found that in 17 patients, the metastases seemed to originate from just one cell – or a small group of genetically similar cells – that had broken away from the original colon tumour early in its development.

Next, researchers combed through data on more than 900 patients with metastatic colon cancer, and 1 800 whose cancer had not spread. All had had their original tumour analysed to detect changes in genes known to be linked to cancer.

The researchers found that certain combinations of gene mutations were strongly related to the odds of metastases.

"It wasn't any single mutation, but specific combinations of mutations, that seemed to tip the balance," Curtis said.

More research needed

For example, mutations in a gene called PTPRT, in combination with certain other mutations, were found almost exclusively in patients with metastatic cancer. Past research has shown that when PTPRT's function is lost, a "cell survival" protein called STAT3 becomes more active.

Curtis said it's possible that a drug that would inhibit STAT3 could prevent metastases.

More research is needed to better understand what genetic drivers cause early metastases – and why some cancer patients never develop metastases, Curtis said.

The study authors are also looking at whether this same phenomenon is true of other types of cancer.

Curtis stressed that the findings do not diminish the importance of colon cancer screening to catch the disease early. Treating the disease in its early stages is always critical.

Weiser made another point: Patients newly diagnosed with colon cancer often feel they have to rush into treatment, thinking the risk of it spreading rises with each day. But if that risk has more to do with tumour genetics than with time, patients may feel less pressure to make an immediate decision.

"You can take the time to consider the options and make sure you get the right treatment," Weiser said.

Image credit: iStock


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