The human body is a mosaic of different genomes

The human body is a complex mosaic made up of clusters of different genome cells – and many of these clusters carry mutations that could contribute to cancer, according to a comprehensive survey of 29 tissue types.

It is the largest study of its kind to date and compiles data from thousands of samples collected from about 500 people. The results, published on June 6 in Science¹, could help scientists better understand how cancer starts and how to detect it earlier.

"We are now aware that we are mosaics" and that a large number of cells in our body already carry cancerous mutations, "says Iñigo Martincorena, a geneticist at the Wellcome Sanger Institute in Hinxton, UK. "These are the seeds of cancer."

Tissue mosaics appear when cells accumulate mutations, due to DNA errors occurring during cell division or exposure to environmental factors such as ultraviolet rays or cigarette smoke. When a cutaneous cell with a given mutation divides, it can create a skin patch genetically different from its neighbors.

Previous studies have revealed high levels of mosaicism in the skin²esophagus³ and blood⁴. These results generally come from the sequencing of specific genes in microscopic tissue samples.

Complex reasons

These studies drew the attention of Gad Getz, a computer scientist biologist at Massachusetts General Hospital in Boston. Getz and his team decided to take a different approach: instead of sequencing DNA from tiny samples, they would exploit a database of RNA sequence data from the GTEx project (Genotype-Tissue Expression). Since the body uses DNA as a template for making RNA sequences, the mutations in DNA are sometimes reflected in RNA.

The decision to study NRA allowed Getz and his colleagues to quickly access data from 6,700 samples taken from 29 tissues collected from about 500 people. But their approach has its disadvantages. All DNA does not code for RNA, so all DNA mutations will not be evident in the RNA sequences. In addition, since the samples used for the GTEx project are relatively large, the DNA signature of small clusters of cells with a single genome could be drowned out by the much larger number of other cells.

Overall, the study found fewer examples of mosaicism in certain types of tissue that would be expected based on previous research. But the key, according to Martincorena, is that the latest analysis has shown that mosaicism is present in a wide range of tissues.

Tissues with a high rate of cell division, such as skin and esophagus, tended to exhibit more mosaicism than tissues with a lower rate of cell division. Mosaicism also increased with age and was particularly prevalent in the lungs and skin – tissues exposed to environmental factors that could damage DNA.

Subtle signals

A gene called TP53 – known to be the "guardian of the genome" – to repair DNA damage – was one of the most common mutation sites. Some changes in TP53 are associated with cancer, but other genes may have to undergo mutations before the cells cause the formation of tumors.

"What we're seeing are some of the first precancerous changes that will then accumulate more mutations," said Erin Pleasance, who is studying cancer genomics at the British Columbia Cancer Agency in Vancouver, Canada. "In the end, a small proportion of them could become cancerous."

Researchers must now find ways to determine which cells will become tumors and which ones are "normal," says Cristian Tomasetti, a mathematician at Johns Hopkins Medicine in Baltimore, Maryland. This could be crucial for improving early detection efforts for cancers.

Tomasetti has developed methods for detecting tumorous DNA circulating in the blood, which researchers hope to use one day to detect the first signs of cancer. But he says his team was initially surprised to find that some of the mutations in their findings – associated with cancer and thus could have indicated the presence of a tumor – came from a group of cells normal blood levels.

"This messy situation is the new normal," says Tomasetti. "The challenge now is to determine up to what point we call something normal."