A study found that healthy cells of the esophagus develop many mutations. (Steve Gschmeissner/Science Source)
Cancer is a disease of mutations. Tumor cells are riddled with genetic mutations not found in healthy cells. Scientists believe it takes five to 10 key mutations for a healthy cell to become cancerous.
Some of these mutations have environmental causes, such as ultraviolet rays and cigarette smoke. Others arise from harmful molecules produced by the cells themselves. Researchers are now taking a closer look at these mutations, to understand how they arise in healthy cells, and what causes these cells to erupt into cancer.
The research has produced some surprises. A large portion of the cells in healthy people carry far more mutations than expected, including mutations thought to be the prime drivers of cancer. These make a cell grow faster than others, raising the question of why full-blown cancer isn’t more common.
“This is quite a fundamental piece of biology that we were unaware of,” said Inigo Martincorena, a geneticist at the Wellcome Sanger Institute in Cambridge, England.
These lurking mutations went unnoticed for so long because the tools for examining DNA were too crude.
But as DNA sequencing grew more sophisticated, Dr. Martincorena and others developed ways of detecting very rare mutations, and they wondered if those might be found hidden in healthy cells.
They began with skin; its cells are battered daily by the sun’s ultraviolet rays, which trigger mutations.
In a 2015 study, the scientists collected skin from cosmetic surgeries on eyelids. They coaxed the top layers of cells, called epithelial cells, from the underlying tissue.
The team fished the DNA from the healthy epithelial cells and sequenced 74 genes known to play a role in the development of cancer. Mutations that are common in cancer genes were remarkably common in these healthy skin cells, too. About one of every four epithelial cells carried a mutation on a cancer-linked gene, speeding up the cell’s growth.
It was possible that skin was peculiar. Maybe inside the body, away from the onslaught of ultraviolet rays, were healthy cells that didn’t carry these key mutations.
The researchers then studied the same 74 cancer-related genes in esophagus tissue. New mutations arose more slowly in the esophagus than in skin. But once those mutations emerged, they caused the esophageal cells to multiply faster than normal esophageal cells. Over time, these rogue cells spread out across the esophagus, forming colonies of mutant cells, known as clones. Although these clones aren’t cancer, they exhibit one of cancer’s hallmarks: rapid growth.
“These mutant clones colonize more than half of your esophagus by middle age,” Dr. Martincorena said. “It was eye-opening for me.”
The mutations seem to have arisen through ordinary aging. The rise of these mutations may just be an intrinsic part of getting older.
Scott Kennedy, a cancer biologist at the University of Washington, said the study also raised questions about efforts to detect cancer at its earliest stages, when cancer cells are still rare. “Just because someone has mutations associated with cancer doesn’t mean actually they have a malignancy,” he said.
Given the abundance of cancer mutations in healthy people, why isn’t cancer more common? A healthy body may be like an ecosystem: Clones with different mutations may arise in it, compete for space and resources, and keep each other in check, Dr. Martincorena said.
If so, fighting cancer might one day be a matter of helping harmless clones outcompete the bad ones.
“It opens up new avenues,” Dr. Martincorena said. “I think knowledge is always a weapon.”