Deletion Some genes can lead to dysregulation of cell growth, so that if they are in a homozygous state, it can lead to the development of cancer. The bcr gene, together with its translocation partner, forms a complex protein that causes constant expression of the enzyme tyrosine kinase, a stimulator of cell division.
For deactivations tumor suppressor gene damage is required in both alleles of the gene, therefore such a recessive mechanism is typical for hereditary forms of cancer, when congenital damage or deletion in one of the alleles is supplemented during life by damage to the paired allele, which leads to the development of a tumor. The table shows characteristics genes that suppress tumor development, distinguishing them from oncogenes.
Among the most studied diseases This type includes Li-Fraumeni syndrome and Wilms tumor. Nadson proposed that retinoblastoma develops in two stages, with the loss of the inherited allele occurring after the loss of the complementary allele. Apparently, the loss of the second allele occurs during the process of recombination or mitotic chromosome nondisjunction.
In patients retinoblastoma The risk of developing osteosarcoma increases 300 times. It is still not clear why these tumors are so strictly restricted to these two locations (bone and eye). The Rb gene is located on chromosome 13ql4.
Distinctive features of oncogenes and tumor suppressor genes
The Wilma tumor gene is located in 11p13 chromosome, and, as with retinoblastoma, the absence of this gene is periodically reported in patients with non-hereditary cancers such as osteosarcoma. Inherited forms of Wilma tumor are quite rare, and 50% of people with damage to this gene do not develop tumors. However, in some patients with non-hereditary forms, a deletion of the 11p13 chain is registered, and studies of polymorphism of the chromosome set show the loss of this chromosomal region in 50% of patients.
Development Li-Fraumeni syndrome caused by a congenital mutation of the p53 gene. Families with this mutation are at risk of developing sarcoma in childhood, early development of breast cancer in women, and an increased risk of brain cancer, adrenal cancer and leukemia in all family members. The p53 protein is a nuclear phosphoprotein that regulates cell cycle. Its sporadic mutations are often observed in cancers of various types.
BRCA1 genes And BRCA2 are tumor suppressor genes for breast cancer. Congenital mutations are transmitted by maternal and paternal chromosomes 17 and 13, respectively. Subsequent loss of the healthy allele results in inactivation of the gene. Both of these genes encode proteins responsible for DNA repair and maintaining the integrity of the cell genome.
The loss of their activity leads to accumulation of genetic errors and, as a consequence, to the development of cancer. Men with mutations in these genes have increased risk get prostate cancer.
Many people suffering have hope of returning to full life and even full recovery. The practical application of the principles of personalized medicine has allowed leading Israeli oncologists to move to a qualitatively new stage in the treatment of this serious illness. Personalized medicine is based on strictly individual approach to the development of a therapy program for each patient, which involves activities such as: studying the characteristics of the cells of the detected tumor; prescription of medications latest generation; experimental testing of treatment regimens, up to the creation of targeted drugs for a specific patient.
Despite the disappointing world statistics that more than half (53.4%) of patients with lung cancer are diagnosed on late stages and their chance of recovery is only 3.4%, I am sure that the survival rate of such patients can be increased to 20% in the near future. This statement by the Chairman of the International Lung Cancer Association, leading oncologist-pulmonologist of the Herzliya Medical Center and the Beilinson Clinic is based on an analysis of the results already obtained in the treatment of patients with lung cancer pathologies.
So, if two decades ago, after the diagnosis of a malignant lung tumor in the late stages of development average duration The life of patients was about 4 months, now this period has increased 10 times - 3.5 years. At the same time, the quality of life of patients has improved significantly. One of important factors Such success is the practical application of the principles of personalized medicine in the treatment of oncological pathologies of the respiratory system.
Some aspects of personalized therapy for lung cancer
Lung cancer is characterized by an aggressive course: the tumor can double in size in just a month, while severe symptoms appear only in the later stages. At the same time, in the recent past, protocols conservative treatment various types this pathology were identical, without taking into account the histology and cytology of the tumor. Based on practical experience, Israeli doctors came to the conclusion that it was necessary to develop individual plans therapy depending on the cytological type cancer cells identified in a particular patient.
Biomolecular analysis for lung cancer
In order to accurately differentiate lung cancer, bronchoscopy is performed with biopsy taken for histological and cytological studies. After receiving a conclusion from the laboratory about the presence of mutagenesis and the detected type of tumor cell mutation, tactics are developed drug treatment with the prescription of biological drugs. Thanks to the use Israeli doctors biomolecular analysis and prescribing targeted therapy based on its results in many patients with last stage Lung cancer life expectancy exceeds 3.5 years.
Currently, targeted therapy for lung cancer pathologies is relevant for approximately 30% of patients. This group includes those who have identified certain types of mutagenesis that can be treated with already created drugs. However Israeli oncologists under the leadership, they continue to study the mechanisms of mutation and develop new drugs, so it is likely that the list of indications for prescribing biological drugs will soon be expanded.
Biological (targeted) therapy for malignant lung tumors
For biological therapy Two types of drugs are used; they differ in the principle of action on the tumor, but have the same final effect. These drugs block the mechanism of cell mutation at the molecular level without providing negative influence on healthy cells, as happens during chemotherapy. A constant targeted effect only on the cells of the tumor itself leads to the cessation of the malignant process after 3-4 months. To maintain this condition, biological medications must be continued throughout life. Biological treatment is prescribed instead of chemotherapy and radiation therapy and has virtually no side effects.
However, gradually (within 1-2 years) the immunity of malignant cells to active ingredients targeted therapy drugs, in this case there is a need for immediate correction of the prescribed treatment. The main method of monitoring the flow tumor process is regular (every 3 months) computed tomography. If during the next examination there is no positive dynamics, a biopsy is performed and, depending on its results, a decision is made on further treatment tactics.
- If a mutation of the EFGR gene is detected (approximately 15% of cases), treatment with one of three drugs licensed by the American FDA is possible: Iressa, Tarceva, Afatinib. These drugs do not have severe side effects, are available in the form of tablets or capsules for oral administration.
- In the presence of ALK/EML4 gene translocation (from 4 to 7 percent of cases), a licensed in Israel is prescribed medicine"Crizotinib".
- To suppress tumor angiogenesis, the drug Avastin is used, which indirectly affects this process by binding to the VEGF protein. Avastin is prescribed in conjunction with chemotherapy, which significantly increases its effectiveness.
Individual choice of an effective treatment program for lung cancer
When developing a treatment regimen for malignant pathology in a specific patient, Israeli specialists focus not only on the results diagnostic tests, in particular histological and cytological studies of tumor cells. They choose a therapy program and experimentally using laboratory animals. Fragments of tissue taken from the patient’s tumor are implanted into several mice, then each of the 5-6 sick individuals is treated according to one or another plan with the prescription of both already tested and new drugs that are in the clinical trials. The patient is treated with a therapeutic program that has proven to be most effective in treating laboratory mice.
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Comments6
I see medicine has truly entered the 21st century. For a very long time, doctors treated conservatively “the old fashioned way” and nothing fundamentally new was invented. I don’t know what this is connected with, they say that everything in the world is cyclical and a new cycle of active development of medicine may have begun, but I really am observing a sharp leap forward, especially in the field of oncology. Many completely new drugs have begun to be developed that treat in a fundamentally new way, many new methods early diagnosis. I would like to see the time when cancer treatment will be simple and elementary, like the flu, and people will remember terrible methods surgical removals sick organs, like medieval horrors))
I heard about a biological cure for cancer. They say very effective method. But from the article, as I understand it, this treatment is not suitable for everyone and as a result, the body gets used to the medicine, that is, roughly speaking, after two years (based on the article), you need to return to the old tried and tested chemical medicines. It is then interesting to know how the patient’s body and the tumor react to chemotherapy “in the old way” after treatment biological drugs and how does relapse generally occur - gradually or abruptly, violently and aggressively? After all, this determines how justified the use of these new drugs is in principle.
If you follow what is written in the article, it turns out that “life expectancy exceeds 3.5 years” and “gradually (over 1–2 years) the immunity of malignant cells to active substances is formed.” That is, life expectancy increases exactly as long as the new medicine works until you get used to it. From here I can draw conclusions that, in principle, this medicine does not cure or destroy cancer cells, it only heals or keeps cancer from further development, but there comes a point of return and the medicine can no longer control the cancer, after which the reverse unfolding of events occurs. Personal IMHO, it’s good that they found how to extend the life of patients by 3.5 years, but they should find something to kill the cancer itself, and not hold it back.
Sergey, 3.5 years old, this is of course not 10-20 years, but it is a chance and it is an opportunity. Nowadays medicine is developing very quickly, dozens of new treatment methods are found every year and medicines. In these 3.5 years, maybe they will be able to improve this medicine, maybe they will be able to find a new, even better one. This is a chance to survive. People who have this disease struggle every day and enjoy every minute of life. When there is no threat to it, we do not know how much it is worth. And not in money, but in minutes of life. But we must fight, because new methods are being found in this fight, and I believe that the moment will come when humanity will completely defeat cancer. But this takes time. And if we thought that an extra day doesn’t matter, then we probably still wouldn’t have been able to treat the flu.
Bad trouble is the beginning. Let life expectancy increase for now by three and a half years, and then, lo and behold, they will be able to live up to 5 years, and then more and more. The main thing is that it is a full life, and not a prolongation of torment.
Cancer claims millions of lives every year. Cancer is the second leading cause of death after cardiovascular diseases, and in terms of the fear that accompanies it, it is definitely the first. This situation has arisen due to the perception that cancer is difficult to diagnose and almost impossible to prevent.
However, every tenth case of cancer is a manifestation of mutations inherent in our genes from birth. Modern science allows you to catch them and significantly reduce the risk of disease.
Experts in the field of oncology tell us what cancer is, how much heredity affects us, who should genetic testing as a preventative measure and how it can help if cancer has already been detected.
Ilya Fomintsev
Executive Director of the Cancer Prevention Foundation “Not in vain”
Cancer is essentially genetic disease. Mutations that cause cancer are either inherited, and then they are present in all cells of the body, or they appear in some tissue or specific cell. A person may inherit from their parents a specific mutation in a gene that protects against cancer, or a mutation that itself can lead to cancer.
Non-hereditary mutations occur in initially healthy cells. They occur under the influence of external carcinogenic factors, such as smoking or ultraviolet radiation. Cancer mainly develops in people mature age: the process of occurrence and accumulation of mutations can take several decades. People go through this path much faster if they inherited a defect at birth. Therefore, in tumor syndromes, cancer occurs at a much younger age.
This spring a wonderful one came out - about random errors that arise during the doubling of DNA molecules and are the main source of oncogenic mutations. In cancers such as prostate cancer, their contribution can reach 95%.
Most often, the cause of cancer is precisely non-hereditary mutations: when a person has not inherited any genetic defects, but throughout life, errors accumulate in the cells, which sooner or later lead to the formation of a tumor. Further accumulation of these damages already inside the tumor can make it more malignant or lead to the emergence of new properties.
Despite the fact that in most cases cancer occurs due to random mutations, we must take the hereditary factor very seriously. If a person knows about the inherited mutations he has, he can prevent the development of a specific disease for which he is at very high risk.
There are tumors with pronounced hereditary factor. These are, for example, breast cancer and ovarian cancer. Up to 10% of these cancers are associated with mutations in the BRCA1 and BRCA2 genes. The most common type of cancer among our male population, lung cancer, is mostly caused by external factors, and more specifically, smoking. But if we assume that external reasons disappeared, then the role of heredity would be approximately the same as in breast cancer. That is, in relative terms for lung cancer, hereditary mutations are visible rather weakly, but in absolute numbers this is still quite significant.
In addition, the hereditary component manifests itself quite significantly in stomach and pancreatic cancer, colorectal cancer, brain tumors.
Anton Tikhonov
scientific director of the biotechnology company yRisk
Most cancers arise from a combination of random events at the cellular level and external factors. However, in 5-10% of cases, heredity plays a predetermining role in the occurrence of cancer.
Let's imagine that one of the oncogenic mutations appeared in a germ cell that was lucky enough to become a human. Each of the approximately 40 trillion cells of this person (and his descendants) will contain a mutation. Consequently, each cell will need to accumulate fewer mutations to become cancerous, and the risk of developing a certain type of cancer in a mutation carrier will be significantly higher.
An increased risk of developing cancer is passed down from generation to generation along with a mutation and is called hereditary tumor syndrome. Tumor syndromes occur quite often - in 2-4% of people, and cause 5-10% of cancer cases.
Thanks to Angelina Jolie, the most famous tumor syndrome has become hereditary breast and ovarian cancer, which is caused by mutations in the BRCA1 and BRCA2 genes. Women with this syndrome have a 45-87% risk of developing breast cancer, while the average risk is much lower at 5.6%. The likelihood of developing cancer in other organs also increases: the ovaries (from 1 to 35%), the pancreas, and in men also the prostate gland.
Almost everyone has hereditary forms cancer. Tumor syndromes are known that cause cancer of the stomach, intestines, brain, skin, thyroid gland, uterus and other less common types of tumors.
Knowing that you or your relatives have a hereditary tumor syndrome can be very useful in order to reduce the risk of developing cancer, diagnose it early early stage, and more effectively treat the disease.
Carriage of the syndrome can be determined using a genetic test, and the following features of your family history will indicate that you should take the test.
Multiple cases of the same type of cancer in a family;
Diseases in early given indication age (for most indications – before 50 years);
A single case of a specific type of cancer (for example, ovarian cancer);
Cancer in each of the paired organs;
A relative has more than one type of cancer.
If any of the above are common in your family, you should consult with a geneticist who will determine if there is a medical indication for taking a genetic test. Carriers of hereditary tumor syndromes should undergo thorough cancer screening in order to detect cancer at an early stage. And in some cases, the risk of developing cancer can be significantly reduced through preventive surgery and drug prophylaxis.
Despite the fact that hereditary tumor syndromes are very common, Western national systems Healthcare has not yet introduced genetic testing for mutation carriers into widespread practice. Testing is recommended only if there is a specific family history that suggests a particular syndrome, and only if the person is known to benefit from testing.
Unfortunately, this conservative approach misses many carriers of the syndromes: too few people and doctors suspect the existence of hereditary forms of cancer; high risk the disease does not always manifest itself in family history; Many patients do not know about their relatives' illnesses, even when there is someone to ask.
All this is a manifestation of modern medical ethics, which states that a person should only know what will bring him more harm than good.
Moreover, doctors reserve the right to judge what benefit is, what harm is, and how they relate to each other, exclusively to themselves. Medical knowledge is the same interference in worldly life as pills and operations, and therefore the measure of knowledge should be determined by professionals in bright clothes, otherwise nothing will happen.
I, like my colleagues, believe that the right to know about one’s own health belongs to people, not to the medical community. We do genetic testing for hereditary tumor syndromes so that those who want to know about their risks of developing cancer can exercise this right and take responsibility for their own life and health.
Vladislav Mileiko
Director of Atlas Oncology Diagnostics
As cancer develops, cells change and lose their original genetic “look” inherited from their parents. Therefore, to use the molecular features of cancer for treatment, it is not enough to study only inherited mutations. To find out weak spots tumors, molecular testing of samples obtained from biopsy or surgery should be performed.
Genomic instability allows a tumor to accumulate genetic abnormalities that may be beneficial to the tumor itself. These include mutations in oncogenes - genes that regulate cell division. Such mutations can greatly increase the activity of proteins, make them insensitive to inhibitory signals, or cause increased enzyme production. This leads to uncontrolled cell division, and subsequently to metastasis.
what is targeted therapy
Some mutations have known effects: we know exactly how they change the structure of proteins. This makes it possible to develop drug molecules that will act only on tumor cells, and will not destroy normal cells of the body. Such drugs are called targeted. For modern targeted therapy to work, it is necessary to know what mutations are in the tumor before prescribing treatment.
These mutations can vary even within the same type of cancer (nosology) in different patients, and even in the tumor of the same patient. Therefore, for some drugs, molecular genetic testing is recommended in the instructions for the drug.
Determining the molecular changes of a tumor (molecular profiling) is an important link in the clinical decision-making chain, and its importance will only increase over time.
To date, more than 30,000 studies of antitumor therapy are being conducted around the world. According to various sources, up to half of them use molecular biomarkers to include patients in a study or to monitor them during treatment.
But what benefits does molecular profiling provide to the patient? Where is his place in clinical practice Today? Although testing is mandatory for a number of drugs, this is just the tip of the iceberg. modern capabilities molecular testing. Research results confirm the influence of various mutations on the effectiveness of drugs, and some of them can be found in the recommendations of international clinical communities.
However, at least 50 additional genes and biomarkers are known, the analysis of which may be useful in choosing drug therapy(Chakravarty et al., JCO PO 2017). Their definition requires the use modern methods genetic analysis such as high throughput sequencing(NGS). Sequencing makes it possible to detect not only common mutations, but also to “read” the complete sequence of clinically significant genes. This allows us to identify all possible genetic changes.
At the stage of analyzing the results, special bioinformatics methods are used that help identify deviations from the normal genome, even if an important change occurs in a small percentage of cells. The interpretation of the obtained result should be based on the principles evidence-based medicine, since the expected biological effect is not always confirmed in clinical studies.
Due to the complexity of conducting research and interpreting results, molecular profiling has not yet become the “gold standard” in clinical oncology. However, there are situations in which this analysis can significantly influence the choice of treatment.
The possibilities of standard therapy have been exhausted
Unfortunately, even with the right treatment, the disease can progress, and there is not always a choice alternative therapy within the standards for this cancer disease. In this case, molecular profiling can identify “targets” for experimental therapy, including clinical trials(for example TAPUR).
the range of potentially significant mutations is wide
Some cancers, such as non-small cell lung cancer or melanoma, are known to have many genetic alterations, many of which may be targets for targeted therapy. In this case, molecular profiling can not only expand the choice possible options treatment, but also help set priorities when choosing drugs.
Rare types of tumors or tumors with an initially poor prognosis
Molecular research in such cases helps to determine more a full range of possible treatment options.
Molecular profiling and treatment personalization require the collaboration of specialists from several fields: molecular biology, bioinformatics and clinical oncology. Therefore, such research, as a rule, costs more than usual laboratory tests, and its value in each specific case can only be determined by a specialist.
Genetic diversity cancerous tumor turned out to be much more than the most daring calculations showed - a three-centimeter tumor can contain about a hundred thousand mutations!
Cells become cancerous due to the accumulation of mutations: changes in gene sequences lead to the fact that the wrong proteins are synthesized in the cell, including those that control cell division, resulting in a malignant tumor. It is known that there are quite a lot of mutations in cancer cells, and that it is precisely due to mutational diversity that cancer can resist a variety of treatment regimens. But how much is a lot? Is it realistic to count the number of mutations in a tumor, given that its different cells may differ from each other to varying degrees in their mutational profile?
Researchers from Medical center The University of Chicago and the Genomic Institute in Beijing tried to count mutations in a small human liver tumor: its size was about 3.5 cm in diameter, and it consisted of more than a billion cells. 300 samples were taken from her for DNA analysis. After the mutations were counted in each of the three hundred zones, the result was extrapolated to the entire tumor, and it turned out that that in total there should be about 100,000 (!) DNA damage, corresponding to the coding regions of genes (that is, those in which information about the amino acid sequence of proteins is encrypted). This value exceeded the most daring calculations - until now it was believed that cancer cells differ from healthy cells by several hundred or several thousand mutational defects (the limit estimate was only 20,000 mutations). The results of the study were published in the journal Proceedings of the National Academy of Sciences.
Of course, it should be remembered that mutations are not evenly distributed, and most of them occur at a fairly low frequency. The authors of the work themselves say that 99% of different mutations occur in less than a hundred cells, and cells with rare genetic defects prefer to be together. Anyway, new data tells us that in a cancer tumor there are a lot of mutations “in reserve”, for which there is obviously no urgent need, which are not under selection pressure, that is, they do not represent a vital necessity for the cancer cell. It is already well known that tumors have beneficial (for cancer) mutations, or driver mutations that help the tumor grow, and “passenger” mutations that have no effect on growth and simply pass from generation to generation. a long time ago, but no one would have thought that cancer could have such great genetic diversity.
This poses a huge problem for medicine: as we said at the beginning, cancer can survive thanks to mutations that provide resistance to drugs, and with such a huge range of mutations, it will be quite easy to find the desired mutation; some “passenger” mutation will suddenly turn out to be very necessary in changed conditions - for example, when changing the treatment regimen. (Indeed, previous studies have shown that clinical prognosis worsens with increasing tumor genetic diversity.) So with anti-cancer therapy, you need to get rid of absolutely all cancer cells as quickly and as completely as possible, which is very, very difficult.
