Cancer develops due to mutations in our DNA. However, until now, little has been known about how mutations build up in healthy tissue over time. A new study provides fresh detail.
As people age, mutations in their DNA slowly build up. Mutations in healthy tissue are known as somatic mutations.
Because cancer is the result of an accumulation of genetic mutations, understanding how these add up over time is crucial to understanding how the disease starts its journey.
This slow, incremental stockpiling of mutations is probably an important part of the aging process, too.
Until recently, it has been challenging to chart precisely how somatic mutations behave over time; this is predominantly due to technical challenges.
A new paper, published earlier this week in the journal Science, takes the first in-depth look at how cells mutate and compete with each other in healthy tissue over the course of a lifespan.
Charting mutations in healthy cells
The researchers, from the Wellcome Sanger Institute and MRC Cancer Unit at the University of Cambridge, both in the United Kingdom, sampled healthy tissue from the esophagi of nine individuals aged 20–75. None of these people had any history of esophageal cancer or other medical issues with that part of their body.
Next, they carried out whole-genome sequencing to map the presence of mutated cells in these healthy samples.
They found that, to their surprise, people in their 20s had hundreds of mutations in each cell. In older participants, this figure rose to more than 2,000 per cell. However, the researchers found that only changes in specific genes had a significant impact.
Mutations in some genes gave the cells a competitive advantage, meaning that, as they divided and conquered, they outcompeted cells without the mutation and colonized large patches of tissue; this created a patchwork of mutant cells.
By middle age, more than half of the cells in a healthy esophagus might carry mutations in cancer genes.
Joint lead author, Prof. Phil Jones, says, "Under the microscope, the esophageal tissue looked completely normal — it came from healthy individuals who had no signs of cancer. After studying the genetics, we were shocked to see that the healthy esophagus was riddled with mutations. We discovered that by the time an individual reaches middle age, they probably have more mutant than normal cells."
Digging into cancer-related genes
The scientists were particularly interested in a mutated gene known as TP53. This gene is present in virtually all esophageal cancers. They found that it had already mutated in 5–10 percent of normal cells. The authors believe that cancer might develop from this subset of cells.
Another gene of interest was the NOTCH1 gene, which is essential in cell division. By middle age, almost half of all cells had mutations in this gene.
In fact, NOTCH1 mutations were more prevalent in healthy tissue than in esophageal cancer. This raises new questions about the role of genes in cancer; contrary to popular opinion, NOTCH1 mutants might protect against cancer.
"For years we have sequenced cancer genomes and looked for genes that are commonly mutated across patients. We assumed that the common mutations are the ones driving the cancer," explains joint first author, Dr. Jo Fowler.
"However," continues Dr, Fowler, "Now we have looked at normal tissues, we were surprised to find that a gene commonly associated with esophageal cancer, NOTCH1, was more mutated in normal cells than cancer cells."
This could change the way researchers approach the study of tumorigenesis, which is the formation or production of a tumor or growth.
"These results suggest that scientists may need to rethink the role of some cancer genes in the light of sequencing normal tissues."
Dr. Jo Fowler
The current study provides a new way to think about the origins of esophageal cancers. The fact that a "healthy" esophagus was shown to be a dense network of mutant cells carrying cancer-related gene mutations might spur researchers in new directions.
The findings shed new light on the way in which our cells develop as we age. As joint lead author, Dr. Inigo Martincorena from the Wellcome Sanger Institute says, "It is remarkable that we have been unaware of the extent of this phenomenon until now."
Dr. Martincorena continues, "It also raises many questions about how these mutations may contribute to aging and other diseases, opening interesting avenues for future research."
The spotlight of cancer research may begin to shift further toward the study of healthy tissue; Prof. Karen Vousden from Cancer Research U.K., who part-funded the study, says, "As cancer researchers, we can't underestimate the importance of studying healthy tissue."