Oncogenes in a jar
Data from the largest database of oncogenic mutations are classified
Phys Tech blog, Naked Science
Based on the genomic data of 10,000 patients, researchers from the Laboratory for the Development of Innovative Medicines and Agrobiotechnologies of the MIPT School of Biological and Medical Physics calculated the number of oncogenic mutations of various molecular and functional types in different types of cancer, in patients of different demographic and clinical groups. The main purpose of the classification was to divide mutations into significant and insignificant ones in order to further simplify the selection of the necessary therapy.
The results of the study are published in the journal PLOS Genetics (Vyatkin et al., Comprehensive patient-level classification and quantification of driver events in TCGA PanCanAtlas cohorts). "Cancer mortality accounts for about half of all deaths, and mutations and various chromosomal defects are considered the main cause and at the same time the mechanism of cancer development.
We analyze them to identify targets for potential therapeutic effects in order to know which genes and which proteins to influence," says Alexey Belikov, one of the authors of the study, senior researcher at the Laboratory for the Development of Innovative Medicines and Agrobiotechnologies at MIPT.
To classify mutations, including significant and insignificant ones, scientists have developed four proprietary bioinformatic algorithms, with the help of which they processed genomic data from the largest database of patients with oncopathology — TCGA PanCanAtlas.
"One of the four algorithms that we have created identifies oncogenic chromosomal defects that occur in tumors. Until now, there was only one such program in the world — the Americans," explains Alexey Belikov. — As a result, it turned out that our algorithm detects defects that for some reason were not detected by an existing program. Moreover, these defects are confirmed by other scientific studies."
Among a large number of mutations and various chromosomal abnormalities, new algorithms have made it possible to identify those that are significant for the development of a cancerous tumor. In particular, it was found that in some types of cancer, only one oncogenic mutation affects the development of the tumor, and in some — two dozen.
"If you take a sample of a particular patient's tumor and sequence it, the analysis can show hundreds of mutations, and you will have to pick up inhibitors of hundreds of proteins for treatment, which is not possible," says Alexey Belikov. "Our analysis shows that, on average, 12 mutations per tumor are significant, and this allows us to further influence exactly the right proteins, and not act blindly."
The study made it possible to determine with high accuracy the number of different types of oncogenic mutations. Classifications were carried out by gender and age of patients, type and stage of cancer, as well as by other criteria.
In addition to the answers, the classification raises a large number of questions and opens up prospects for further work. For example, why is there such a big difference in the number and composition of oncogenic mutations between cancer types? Why is it enough to initiate thyroid cancer with only one oncogenic mutation, and with bladder carcinomas there are two dozen?
Why do some cancers have no changes in oncogenes, while others have no changes in tumor suppressors? Are these differences explained by the different tissue microenvironment to which these tumors must adapt? Why then, for some patients with the same type of cancer, one oncogenic mutation is enough for the development of a detectable tumor, whereas in others tumors are not diagnosed until dozens of mutations have accumulated? All these questions have yet to be answered.
Scientists hypothesize about some of these questions in their research; others, such as the reason for the high variability in the number and composition of oncogenic mutations between cancer types, remain unanswered. "In general, our work brings some clarity to the distribution of oncogenic mutations of various classes in various demographic and clinical groups of patients," Alexey Belikov summarizes.
"Our research is of great importance for the development of personalized oncology. In continuation of this work, we have already developed a new bioinformatic approach to determining the oncogenic strength of mutations in key genes. Having proved the importance of mutations of these genes for the malignant degeneration of normal cells in vitro and in vivo, we will be able to shed light on the molecular mechanisms of the occurrence and development of cancer, which in the future will allow for the optimal choice of targets for personalized therapy of each oncological patient," explains Sergey Leonov, head of the laboratory for the development of innovative medicines and agrobiotechnologies at MIPT.
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