Ruminations

Researching the Genesis of Cancer

"This is quite a fundamental piece of biology that we were unaware of."
"These mutant clones colonize more than half of your esophagus by middle age. It was eye-opening for me."
"It [helping harmless clones to outcompete the bad ones] opens up new avenues [in fighting cancer]. I think knowledge is always a weapon."
"We have found that genetic mutations associated with cancer are widespread in normal tissues, revealing how our own cells mutate, compete and evolve to colonize our tissues as we age. Given the importance of these mutations to cancer, it is remarkable that we have been unaware of the extent of this phenomenon until now."
"While the work sheds light on early cancer development, it also raises many questions about how these mutations may contribute to aging and other diseases, opening interesting avenues for future research."
Dr. Inigo Martincorena, geneticist, Wellcome Sanger Institute, Cambridge, England

The image above shows a summary representation of what 1cm2 of normal oesophagus looks like in the 9 individuals, sorted by age. We see large differences in burden, clone sizes and even preference to mutate certain genes across patients. Dr. Inigo Martincorena

New research by a team headed by Inigo Martincorena has come up with some unexpected results, basically that cells in healthy people carry more mutations than ever thought and these include mutations in a large portion of cells felt to represent the primary drivers of cancer which incite some cells to grow faster than others, the hallmark of cancerous cells as they run amok, growing and replicating faster than the body's immune system can detect and target them. That being so, the puzzle is that despite this recognition cancers are not more common among any given population.

The reason that these mutations were not picked up and studied is simply that the tools to examine DNA were too crude. Dr. Martincorena and other researchers gradually developed new methods enabling them to detect rare mutations as DNA sequencing became more sophisticated. As they uncovered the presence of these mutations it occurred that they might also be found to be present and hidden in healthy cells. Starting with the body's largest organ, the skin, where cells are daily assaulted by the ultraviolet rays of the sun known to trigger mutations, this is where they began.

Scientists collected skin from cosmetic surgeries in eyelids in a 2015 study, gently prying away the top layers of cells (epithelial cells) from the underlying tissue. DNA from healthy epithelial cells were were isolated, then researchers sequenced 74 genes recognized as playing a role in the development of cancer. In these healthy skin cells mutations common in cancer genes were discovered with one of every four epithelial cells carrying a mutation on a cancer-linked gene, expediting the cell's growth.

Researchers speculated that this situation was peculiar to skin alone and that it was likelier that within the body where ultraviolet rays were unable to penetrate, healthy cells without key mutations such as those found in the skin would be far more likely to be present. But when the same74 cancer-related genes in esophagus tissue were found albeit more gradual to develop in the esophagus than in skin, it became obvious this was not the case. Given time the rogue cells spread across the esophagus to form colonies of mutant cells, identified as clones.

Clones exhibit one of cancer's hallmarks; rapid growth, though they are not themselves cancerous. Ordinary aging it seems, leads to the rise of mutations leading to further speculation that their presence may represent an intrinsic physiological change related to growing old. According to Scott Kennedy, a cancer biologist at University of Washington, the study raises questions surrounding efforts to detect cancer at its earliest stages. "Just because someone has mutations associated with cancer doesn't mean actually they have a malignancy", he explained.

The conundrum facing researchers is that, given the plenitude of cancer mutations within healthy people, why is it then that cancer does not present more frequently than it does? And the answer may well be that a healthy body may be akin to an ecosystem where clones with variant mutations may arise, compete for space and resources and thus maintain a balance, none of them able to surmount the influence of the others.

That being the case, Dr. Martincorena muses, fighting cancer may one day become invested in a therapeutic response where aiding harmless clones to outcompete the bad ones becomes the first line of defence against cancer onset.