Such different mutations

Scientists have discovered a mosaic of mutations in normal human tissues

Andrey Ukrainsky, N+1

Scientists have made an extensive review of macroscopic populations of clones of cells that carry various mutations, but are located in healthy human tissues. Some of these mutations are associated with cancer risk. According to their findings published in Science (Yizhak et al., RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues), normal tissues usually do not consist exclusively of normal cells, they include a mosaic of mutations that continue to develop throughout life. According to the authors, the study provides the basis for identifying links between clonal growth, exposure to external factors, aging and disease risk.

During the lifetime of the organism, cells accumulate somatic (non-hereditary) mutations. Most of them are considered harmless or relatively safe, but some increase the resistance and survival of cells, which leads to their clonal reproduction (expansion) in tissues. This process is associated with aging, the development of diseases of the cardiovascular and nervous systems, as well as cancer. Over time, quantity can turn into quality: the accumulation of certain driver mutations can lead to uncontrolled cell growth.

There are gaps in the knowledge about the initial stages of cancer development, which scientists have been trying to fill in recent years by studying healthy tissues and precancerous lesions. A few years ago, clonal expansion was discovered in normal blood, including clones with genes that may be responsible for the development of blood tumors. Ultra-deep sequencing showed the presence of cancer mutations in normal tissues of the skin and esophagus (scientists focused on 74 genes). However, the question of which of the detected clones will actually develop into cancer remains open.

In the introduction to the new study, Keren Yizhak from the Broad Institute of the Massachusetts Institute of Technology and Harvard University and colleagues write that the available data indicate the need for a complete mapping and study of the prevalence of clonal expansion in different human tissues. To find out how common the cells of mutant lines are and how active the mutated genes are in normal tissues, the scientists sequenced the RNA of 6,700 samples of 29 tissues taken from 488 people.

RNA analysis made it possible to learn not just about DNA mutations, but about those that are expressed. This approach makes it possible to detect only relatively large populations of clones. Previous studies focused on detecting a certain limited set of genes in healthy tissues, but did not address their activity. To detect somatic DNA mutations in the study of RNA, scientists have developed a new computational pipeline RNA-MuTect. They took information about the normal expression of genes in various tissues from the project data Genotype-Tissue Expression, which were obtained in the study of hundreds of healthy people.

The authors found 8870 somatic mutations in 37 percent of tissue samples from 95 percent of the study participants. According to the calculations of scientists, taking into account possible false positive results, more than four mutations were present in 374 samples of 24 tissues, among them – there were 13 mutations in 106 samples of 13 tissues. Mutations in genes associated with the development of cancer were found in 33 percent of the study participants, in three percent of tissue samples.

The number of mutations in 28 of the 29 studied tissues. Each tissue sample is marked with a circle, horizontal black stripes show the average number of mutations in each tissue. A drawing from an article in Science.

In the areas of the skin that are most exposed to the sun, in the esophageal mucosa and in the lungs, the greatest number of accumulated mutations were found compared to other tissues. The authors emphasize that these three tissues are most intensively affected by external mutagenic factors. Both in the skin and in the esophagus, the authors found a link between the number of mutations in normal tissues and age. Scientists suggest that the absence of an expressive relationship between the number of mutations with age in the lung tissue may be masked by exposure to external mutagens (smoking, polluted air). Scientists also found that the rate of cell proliferation in various tissues was associated with the number of mutations accumulated in them: for example, in the esophagus and skin, it was higher than in muscles and the brain.

The authors note that they found significantly fewer clonal expansions than studies that focused on microscopic populations of clones. They attribute this to the possible omission of mutations with a low level of expression, as well as to the fact that, apparently, in most cases, clones remain microscopic and their size does not allow them to be detected by RNA sequencing.

According to the study, TP53 and NOTCH1 genes were the most frequently mutated, but these mutations were still detected less frequently than in previous studies of microscopic clone populations. Scientists believe that this indicates that, perhaps, these mutations of these genes cannot lead to the growth of a population of clones larger than a certain size without additional input from genetic, epigenetic or external factors.

Cristian Tomasetti from the Department of Oncology of the Interdisciplinary Cancer Center Sidney Kimmel in the article Mutated clones are the new normal, which is published in the same issue of Sciepse, indicates that the data of Yizhak and co-authors emphasize the need for a better understanding of the temporal dynamics of somatic mutations and clonal expansion in normal tissues. "This is necessary in order to satisfactorily divide people into risk groups and predict the risk of developing cancer depending on age. Even such a promising method of early cancer diagnosis as sequencing extracellular DNA from blood to detect early signs of cancer anywhere in the body critically depends on what is normal and what is not," he writes.

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