Biologists for the first time measured the irreversible risk of cancer

Anna Kaznadzei, N+1

Here the article about the role of random mutations in oncological diseases is retold in a completely different way than in the material "Dangerous Copying" just published on our website – VM.

Mutations that can cause cancer are usually classified into two main categories: hereditary and those that have arisen as a result of environmental exposure. American scientists have shown that the third source of mutations is no less significant – the inevitable errors that occur during DNA doubling. In some cases, their contribution is more than 95 percent. The study is published in Science.

According to the latest data from the International Association for Cancer Research (IARC), cancer is the most common cause of death on our planet. One of the main reasons for their occurrence are changes in the DNA sequence, which are called mutations. Mutations can be inherited from parents (H-mutations) or as a result of environmental influences (C-mutations) – for example, due to smoking or exposure to radioactive radiation. In addition, random errors (P-mutations) also occur during the normal process of DNA replication, for example, when the polymerase enzyme, building a new chain according to the template of an existing one, mistakenly inserts the wrong nucleotides-letters there. Other causes of P-mutations include quantum effects, the influence of endogenous reactive oxygen species and hydrolytic deamination of nucleotides.

It is estimated that every time a human cell divides, it has about three new mutations. Most of these mutations pass completely unnoticed by the organism, moreover, replication errors are a necessary driving force of evolution; however, it is known that some of these mutations or their combinations may be carcinogenic. The quantitative contribution of P-mutations to the occurrence of dangerous changes has so far been, however, not entirely clear.

Cells that have already become cancerous stop their normal work and begin to divide rapidly and uncontrollably, which leads to the appearance of tumors. Ordinary cells have a completely different ability to divide. The epithelium, for example, does this all the time, and the formed neurons never do it at all, and when trying to force them to divide in the laboratory, they die. The risk of developing cancer in different tissues is also completely different, and this is what prompted the researchers to think that the reason may lie in the process of DNA doubling before cell division.

In the experiment, scientists investigated the relationship between the rate of replication of stem cells and the likelihood of cancer. To do this, they estimated the number of shared stem cells in patients of different ages and correlated these numbers with medical data from the IARC database. Assessing the contribution of different processes leading to the appearance of dangerous mutations, the researchers assumed that P-mutations in individuals of the same age would be approximately the same number, since the division of stem cells in all occurs at approximately the same rate, while the levels of H-mutations or C-mutations in different people can vary greatly. In order to take into account the influence of the external environment, the area of research initially conducted in the USA was expanded to 69 different countries and as a result covered a wide variety of environmental conditions, 17 types of cancers and patients of all ages.

It turned out that the probability of getting a certain type of cancer depends very much on the ability of the cells of the corresponding tissue to divide, and, thus, the proportion of replication errors among carcinogenic mutations is very high. The coefficient of dependence of the risk of developing the disease on the rate of stem cell division everywhere exceeded 0.7. The median of this correlation was 0.8. These are amazing figures – scientists assumed that the contribution of different environmental conditions would make such an analysis impossible, but the influence of P-mutations turned out to be unexpectedly strong.

To quantify the proportion of P-mutations among all carcinogenic changes in human DNA, a separate independent study was conducted. In the model under study, the numbers of H-mutations and C-mutations were initially taken as zero. In such a beautiful hypothetical population, cleared of hereditary cancer mutations and living in ideal environmental conditions, cancer will still occur – as a consequence of P-mutations. By adding various factors to such a model that increase the influence of C-mutations, and taking into account already known H-mutations, it is possible to understand which mutations appeared from where when comparing the results.

In order to obtain the corresponding numbers, scientists first used the results of genomic sequencing and epidimeological data for patients with lung adenocarcinoma (there are no known hereditary mutations for it, but a very strong correlation with smoking and a less strong one with ionizing radiation, air pollution, "passive" smoking and other environmental factors). The calculations were carried out as follows: if a patient who smoked, the number of mutations was, for example, three times greater than a non-smoking patient, then the contribution of C-mutations for them was estimated as two-thirds, and P-mutations – as one-third. Thus, the contribution of both types of mutations was calculated for a sample of 20 patients. It turned out that the number of carcinogenic P-mutations is on average 35 percent. According to Cancer Research UK, 89 percent of cases of lung adenocarcinoma can be prevented if you do not smoke, but this does not contradict the fact that P-mutations in non-smokers will still accumulate at the same rate.

After that, scientists conducted a similar analysis with exomic and epidemiological data concerning pancreatic ductal adenocarcinoma, which can also be prevented by changing living conditions, but only in only 37 percent of cases. H-mutations accounted for about 5 percent of the driver (dangerous) carcinogenic mutations of this type of cancer, while P-mutations accounted for as much as 77 percent.

During the study of the third group of cancers, for which it was known that environmental factors and hereditary factors are usually insignificant for them (for example, prostate, brain or bone cancer), scientists confirmed that the alleged P-mutations in this case account for 95 percent of carcinogenic driver mutations.

The proportion of H-mutations (hereditary), P-mutations (replication) and C-mutations
(environmental exposure) in different types of cancer in women (figure from an article in Science).

In total, 32 types of cancer were studied in this part of the work. For each of them, the proportion of the influence of all three types of mutations was calculated. The contribution of P-mutations to the development of all cancers in the UK, for example, was 66 percent. It is worth noting once again that these data do not contradict the estimates according to which many types of cancer can be prevented by changing environmental conditions. For example, if the proportion of P-mutations is 50 percent, and errors in both copies of the corresponding gene are needed for the development of the disease, then most likely only one of them will appear as a result of the P-mutation, and preventing the second can save a person.

It is important to understand that mutagenesis is a constant process. Scientists note that despite the fact that it is almost impossible to prevent carcinogenic P-mutations, it is necessary to try to track their occurrence, since early diagnosis and timely treatment of cancer diseases lead to a complete recovery of patients much more often than working with patients at late stages. But mutagenesis also has positive aspects. Tasmanian devils, for example, their own new mutations helped to quickly cope with a very dangerous and contagious cancer without any drugs.

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