Present and future of oncogenetics
Genetics against cancer
Irina Reznik, Mednovosti
To date, it is known about more than two hundred diseases associated with hereditary predisposition to cancer, the carrier of mutations is presumably every 180th inhabitant of the planet. Drugs that reduce the risk of developing the disease are a matter of the future, but modern science already allows us to establish the fact of carriage and calculate the degree of this risk. And for treatment – to determine exactly what the tumor is and what are the causes of its appearance.
Personalized approach
Hereditary oncological diseases not only manifest themselves at a fairly early age, but also proceed more aggressively. In addition, patients with a mutation require different treatment than patients who do not have genetic breakdowns. And knowing about the carrier of the fatal gene, which can be detected with the help of molecular genetic testing, can save many lives.
The chemotherapy regimens that existed for a long time in such cases were ineffective. The breakthrough was the emergence of targeted therapy that purposefully affects tumor cells of patients with genetic rearrangements. But there remained the problem of identifying patients who are suitable for such treatment. The decoding of the human genome helped to solve it, the work on which was officially completed in 2003. At the same time, the concept of "personalized medicine" appeared. And today, cancer genotyping is already fully used in oncology with an assessment of the effectiveness of the use of certain targeted drugs.
The selection of targeted therapy is a very important direction in oncology, Kamil Hafizov, head of the scientific group for the development of new diagnostic methods based on high–performance sequencing technologies of the Central Research Institute of Epidemiology of Rospotrebnazdor, told Mednovosti. At the same time, in his opinion, there is not only medical, but also economic sense in these tests: it is wiser to first conduct an analysis for the presence of mutations worth 10-20 thousand rubles than to spend blindly on expensive therapy, which is not shown to everyone.
But while the state does not finance molecular genetic testing, the patient himself or the regional budget pays for it, as, for example, in Moscow.
Fatal mutations
Predisposition to certain types of cancer occurs, in particular, when the BRCA1 and BRCA2 genes are broken, which protect DNA molecules from violations. According to Sergey Tyulyandin, Chairman of the Russian Society of Clinical Oncology (RUSSCO), Deputy Director for Research at the Blokhin Research Institute of Clinical Oncology, the presence of BRCA gene mutations is due to about 15% of ovarian cancer and breast cancer. In addition, 5-10% of patients (regardless of their gender) with malignant tumors of the pancreas and men with prostate cancer are carriers of "broken" genes. For the same reason, breast cancer occurs in men. Healthy men, carriers of BRCA gene mutations are more likely to pass them on to the next generations.
Mutation of the EGFR gene, which plays a key role in tumor pathogenesis, occurs in a quarter of lung cancer patients, and the presence of ALK protein, which contributes to the rapid progression of the disease, occurs in 4-5% of patients. That is, almost 30% of patients have a chance for more effective therapy (60 thousand Russians get lung cancer every year). However, so far, according to Ivan Stilidi, director of the N.N. Blokhin Oncology Research Center, in Russia, the EGFR gene mutation is diagnosed in only 3 thousand out of 15 thousand of its carriers.
Speaking at a meeting of the Presidium of the Russian Academy of Sciences on December 25, he proposed to introduce a state program of molecular genetic testing, which makes it possible to prolong the life of patients with hereditary cancer. This could be done by scaling up the program "Improving molecular genetic diagnostics" implemented by RUSSCO, over the five years of which more than 46 thousand patients have been tested for mutations responsible for lung cancer, ovarian cancer, melanoma and colorectal cancer.
Today, a large number of tests for mutations in the BRCA1 and BRCA2 genes have been developed in the world, Kamil Hafizov said. In addition, there are also extended tests where about 20-30 genes are read, breakdowns in which are also associated with a number of oncological diseases, although the probability of mutations in them is somewhat less. Among the genes often included in these tests: PTEN, CHEK2, NBN, TP53, PALB2 and some others.
At the same time, rarer mutations remain that are not detected in existing test systems. And the way out here is in high–performance sequencing of a new generation of NGS (next-generation sequencing), which allows you to read the entire genome sequence of any living creature and identify its phenotypic features.
Population genomics
Some countries are already implementing programs for genetic certification of the population, a leading employee of the RIKEN Institute of Physico-Chemical Research (Japan) and the head of the department told Mednovosti. Laboratory of Extreme Biology of Kazan Federal University Oleg Gusev. According to him, it is very important for countries with a large ethnic diversity, including Russia, to know the genomic profile of their population. In genetics, there is a concept of "founder effect", when at some point certain mutations associated with diseases originated in a fairly limited area. And for a number of diseases, genetic predispositions to them are associated with mutations that are characteristic of the inhabitants of this territory.
Within the framework of the large project "Hereditary Genomics of the Russian Federation", scientists of the KFU and the Republican Oncological Dispensary are investigating genetic mutations in people whose families have inherited cancer. Until recently, it was believed that almost the entire small spectrum of hereditary mutations associated with breast cancer (the kind that Angelina Jolie was afraid of) was known for Russia, and it was enough just to look at 6-7 point markers in two genes to confidently say whether a patient has hereditary pathogenic mutations associated with cancer. However, it turned out that already 700 km from Moscow, in Tatarstan, this profile of hereditary mutations is completely different.
Therefore, if we focus only on the typical and most frequent mutations for Western Europe and the Slavic population, relatively speaking, Moscow and St. Petersburg, then in many cases they will not be on the territory of Tatarstan, and this creates the danger of false negative values, the scientist said. But the risk of developing the disease is carried by mutations that are not found in other populations. "And here the NGS came to the rescue, which allows us to use not the analysis of point mutations, but to look at the entire BRCA gene and four dozen other genes that are associated with oncology," Gusev notes. Scientists and medical researchers under the leadership of the head. The genetics laboratories of the Marat Gordiev Cancer Center expanded the sample to include patients from Chuvashia, Udmurtia, Bashkiria, Khanty-Mansiysk, Orenburg and Krasnodar in the study. We collected more than fifteen hundred DNA samples and estimated the frequency of mutations of genes involved in hereditary forms of cancer in different regions of the country.
But then the following problem arose – related to the lack of a reference database, that is, a sample of healthy people to compare the detected mutations. "One of the signs that the mutation is pathogenic is that it is rare in the population, otherwise everyone would be sick," the expert explained, "But when geneticists see some kind of frequently occurring mutation in a sample of more than 1.5 thousand cancer patients, there is no certainty that it is the cause of cancer. We have to look at international databases of healthy people and cohorts of clinical samples. But since the genetic profile of the population in Russia is special, the only way to solve this problem is to conduct our own genomic project and create such a base for each nationality of our country."
The future of oncogenetics
Today, global scientific developments are increasingly moving into the category of practical diagnostic solutions. For example, genomic studies of the Kazan Cancer Center, conducted jointly with the Japanese RIKEN, made it possible to identify a dynamic marker by which a primary tumor (in particular, the endometrium) can be assessed for whether metastases will appear after it. It was possible to detect a marker that can predict such a possibility by gene expression (conversion of hereditary information into protein).
"Ideally, this analysis should be carried out right during the operation so that the doctor can decide whether to leave the lymph nodes. Usually they are removed for reinsurance, but in 80% of cases this is not justified," Gusev said. Another promising area that allows tissue analysis right during surgery is the so–called "at the patient's bedside" technology. We are talking about a compact device that will give the result of a genetic tissue test in 20-30 minutes, and this will allow you to correct the operation.
A lot of efforts are directed today to the development of minimally invasive methods for the diagnosis of cancer in the early stages. One of the approaches is diagnostics based on freely circulating DNA in the blood (the so–called liquid biopsy). "Tumor cells release small fragments of DNA into the blood containing mutations that led to the appearance of the tumor,– explains Kamil Hafizov. – The number of such cells is very small against the background of healthy DNA, so their detection by standard methods is almost impossible. But approaches have already appeared that allow us to "catch" such molecules." However, they are still practically not used and are not included in the clinical recommendations.
Meanwhile, the Ministry of Health is betting heavily on applied genetics: in the spring of 2018, at a meeting of the Scientific Council with the participation of the President of the Russian Federation, the head of the department Veronika Skvortsova announced the need to create a network of national genomic centers that will deal not only with genetic diagnostics, but also therapy.
One of these centers, specializing in the diagnosis of cancer at the gene level, will appear in the biomedicine park of the First Moscow State Medical University. Sechenov already this year. According to the rector of the university, Pyotr Glybochko, the center will conduct genome-wide sequencing to identify hereditary syndromes in oncology and mutations leading to the development of cancer. In addition to diagnostics, the genomic center will work on the creation of new drugs – molecular cocktails for the treatment of cancer.
It is expected that at least three more genomic research centers will begin their work by the end of 2020, and all the organizations on the basis of which it is planned to create a national network will be selected in the next six months.
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