Dangerous copying

Cancer mutations occur mostly due to inaccurate DNA copying

Kirill Stasevich, "Science and Life"

Two years ago, researchers from Johns Hopkins University published an article in Science in which they argued that the likelihood of cancer depends on the activity of stem cells.

As you know, the tissues of the body are constantly updated due to the reserve of their own stem cells: they are one in the blood, the intestinal epithelium – others, the skin – others, etc. Their rate of division is different, and the number of divisions that a stem cell undergoes during its lifetime is also different.

On the other hand, as is also well known, different types of cancer have different probabilities: lung tumors are statistically 11 times ahead of brain tumors. Usually such a difference is explained by the influence of lifestyle, ecology or poor heredity. However, according to Cristian Tomasetti, Bert Vogelstein and their colleagues, such a difference in cancer statistics is largely due to differences in stem cells: if stem cells divide more vigorously in some tissue, then the probability of cancer will be greater here.

The work caused a lot of controversy, not least because those who retold it sometimes overlooked one subtlety. Cancers arise due to mutations, but ordinary, differentiated cells that form the basis of the organ and perform all the special work do not divide and do not live too long, and even if they accumulate a lot of potentially oncogenic mutations, the disease will not begin. Stem cells, on the contrary, live for a long time, divide many times and can give rise to a tumor.

The more a cell divides, the more likely it is that the oncogenic mutation that once got into it will work – in it and in its clone descendants. And then the question arises: where can a mutation arise in a stem cell? Until now, it was believed that the main causes of oncogenic mutations are poor ecology and an unhealthy lifestyle; in addition, there are also hereditary reasons when an oncogenic mutation passes from generation to generation.

But cells have another, their own source of mutations – this is the DNA replication (doubling) apparatus. A dividing cell makes a copy of its own genetic material, and the enzymes that do this copying inevitably make mistakes. Most of the errors are corrected by repair systems, but some of them remain uncorrected – it is believed that with each division in the cell there are on average three random mutations that have arisen due to copying errors. Obviously, in stem cells that divide many times, there should be more and more such replicative mutations.

At first, everyone thought that the authors of the article were talking about replicative mutations, that they, and not "lifestyle mutations" and not "ecology mutations", mainly become the reason for cancer. This conclusion looked rather doubtful for many. The authors then clarified that they meant simply the activity of stem cells, which, due to their ability to divide, can give a "green light" to mutations of any origin, even "ecological", even hereditary, even replicative. However, now Tomasetti, Vogelstein and Lu Li have published a new article in the journal Science (Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention, in which they already explicitly state that, yes, the main cause of cancer is precisely those mutations that occurred due to copying errors.

In modern medicine, malignant (and not only malignant) diseases are documented very well, which allows you to perform various scientific studies with the accumulated data. And if in the first work the researchers used cancer statistics only for the USA, now they have taken information on 17 types of cancer in 69 countries. To begin with, they checked whether the correlation between the activity of stem cells and the probability of a particular type of tumor is carried out on a global scale – and it turned out that it is.

For tumors, there are also databases in which their mutational portraits are collected (speaking about the mutational portrait of cancer, it should be remembered that even within the same tumor, the set of mutations in different cells may differ). In DNA, it is possible to recognize defects that occur, for example, due to ultraviolet radiation or tobacco carcinogens, so the researchers had only to build a statistical model in which they could compare the probability of a tumor with different mutations. It turned out that, in general, different types of cancer do not depend too much on hereditary DNA defects – they account for only 5% of the probability that a person will have a tumor. External factors, such as ecology and lifestyle, account for 29%. But the 66% chance of cancer depends on random copying errors.

But in different types of cancer, mutations of different origins occur in different proportions: sometimes they make up only 10%, and sometimes – all 95% of the total number of mutations. However, according to the researchers, even if we consider the option when cancer is more due to external factors, then copying errors will still have a fairly large proportion of malignant probability – as much as 40%.

In other words, cancerous tumors largely arise precisely because of the inevitable mutations that accumulate in stem cells due to molecular DNA copying errors. True, although we said that some "external" mutations can be easily recognized, nevertheless, we do not yet have a tool that would allow us to look at any mutation and say exactly where it came from: because of a copying error, because of some environmental factor, or because offor something else. Let's not forget that mutations in cancer cells interact with each other in different ways, and that as the disease develops, some mutations lose their relevance, as they say, while others, on the contrary, become very necessary for the survival of the tumor.

As for inaccurate copying, this is one of the main tools of evolution – it is due to errors in replication that variants of traits arise, of which, as a result of selection, those remain that work better than others in terms of survival. In this case, cancer is just one by–product of variability, without which life simply could not linger on Earth. It is probably not worth trying to improve the accuracy of copying, however, in order to understand the nature of malignant diseases and to create more effective treatment methods, it would be useful to know what contribution mutations of different origins make to the appearance and development of a tumor.

Portal "Eternal youth" http://vechnayamolodost.ru  27.03.2017