Signs of cancer may appear long before diagnosis, study shows Science

The first signs of cancer can appear years or even decades before diagnosis, according to the most comprehensive investigation to date on the genetic mutations that cause healthy cells to become malignant.

The results, based on samples from over 2,500 tumors and 38 tumor types, reveal a longer-than-expected window of opportunity in which patients could potentially be tested and treated early in the disease.

The work was conducted within the Pan-Cancer Analysis of Whole Genomes project, the most comprehensive study of cancer genetics to date.

“The extraordinary thing is how some of the genetic changes seem to have occurred many years before the diagnosis, long before any other sign that a cancer can develop, and perhaps even in apparently normal tissue,” said Clemency Jolly, co-author of the research based at the Francis Crick Institute in London.

“Unlocking these patterns means that it should now be possible to develop new diagnostic tests that detect signs of cancer much earlier,” said Peter Van Loo, lead co-author, also from the Crick Institute. “There is a window of opportunity.”

The discovery that cancer seeds are often sown many years before the first symptoms arise will not change cancer screening in the immediate term. But it indicates the possibility that those at risk could be identified much earlier.

The study revealed that about half of the first mutations occurred in only nine genes, which means that there is a relatively small pool of common genes that act as trigger factors for cells to diverge from healthy development to a path to cancer. . In the future, it may be possible to detect these mutations using so-called liquid biopsies – genetic tests that detect mutations in floating DNA carried in the blood that can indicate the presence of tumors elsewhere in the body.

“You could try to identify them [early mutations] and do some kind of very sensitive imaging on positive patients, “said Van Loo.” Or even further in the future, one could conceive of methods that really targeted these cells and made them illuminate in an imaging approach or simply kill them at once. It’s a bit of science fiction right now. “

About 363,000 new cases of cancer are reported annually in the UK, according to Cancer Research UK, with the disease causing 165,000 deaths annually.

The team analyzed and sequenced approximately 2,700 whole genomes of cancer samples and mapped mutations in 38 different types of cancer.

While human cells undergo billions of mutations, only a small number of them, called driver mutations, cause cancer. The researchers looked at how many times a single change, or driver mutation, had been replicated and copied to the chromosomes.

Using what they describe as a “carbon dating method”, they were able to reconstruct the order in which the tumor cell genomes began to accumulate errors and eventually bring large segments that have been scrambled or copied. The team found that these mutations occurred “particularly early” in ovarian cancer and in two types of brain cancer, glioblastoma and medulloblastoma.

The analysis is published in Nature as part of a larger collection of 22 articles from the Pan-Cancer project.

Previous research on cancer genetics has focused on the so-called coding regions of the genome, which contain instructions for cells to make proteins.

Lincoln Stein, of the Ontario Institute for Cancer Research in Canada, who is also a member of the steering committee of the Pan-Cancer project, said: “The vast majority of the work so far has been devoted to the protein-coding portion of the genome. That’s only 1%. It’s like trying to put together a 100,000-piece puzzle when you miss 99% of the pieces and there isn’t a puzzle box with a full photo to guide you. “

The latest research provides some of the first detailed insights into the role of the other 99% of our DNA – the “dark matter” of the genome – and how these less studied regions contribute to cancer. The study identifies several important genes that are located outside the coding region. Stein said that these newly identified genes would increase the percentage of patients for whom a carcinogenic mutation could be detected by about two thirds to 95%.

“Before this, we would have been in the dark for about a third of the patients who entered the clinic,” added Stein.

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