Edouard Porta, team leader at the Josep Carreras Leukemia Research Institute, and researchers from the Consortium for Clinical Proteomic Analysis of Tumors (USA) have described how DNA changes in cancer-promoting genes lead to specific dysfunctions of the cellular machinery leading to its oncogenic transformation. Through the integration of genomics (changes in genes), proteomics (abundance of proteins), and phosphoproteomics (the state of activation of proteins), this group of researchers was able to gain concrete insight for the first time into how genetic changes in key genes for cancer development pave the way for cellular malignancy. In a series of four publications in one of the leading research journals, Cell, the researchers describe how DNA changes in cancer-causing genes lead to specific dysfunctions in the cellular machinery that lead to its oncogenic transformation and other consequences. Cancer cells behave very badly. For decades, scientists have tried to understand the causes and causes of this behavior and have described thousands of DNA changes that affect genes that are key in the onset and progression of cancer. His hypothesis was that those genes that lead to cancer were translated into proteins that control important aspects of the internal functioning of the cell, which, when changed, could trigger the so-called hallmarks of cancer or cancer markers, which are these elements. that cause the cell to turn into a tumor. However, the mechanism of cells is much more complex than the genes that make proteins. The researchers wanted to go beyond genomics and used functional proteomics to compare 1,065 genomes from 10 different types of cancer to find out what they have in common in terms of mutations, gene expression, and protein interactions. Their results will lay the foundation for a deeper understanding of cancer in the coming years and help develop new therapeutic strategies based on functional damage to cancer cells. Comparing cancer cells with closely related non-cancer cells from the same patients, the researchers found DNA mutations with significant effects in 59 genes common to all types of cancer. A detailed analysis showed that many changes affected the activity of these genes, increasing or decreasing the abundance of their products (RNA or protein). In a second paper in The Cancer Cell, Porta and the rest of the researchers found that epigenetic changes also affect gene activity, with the same results. As expected, genes known to suppress tumor progression (called tumor suppressor genes) tended to be underactive, while genes known to promote cancer progression (called oncogenes) tended to be overactive. The identification of cancer driver genes is of paramount importance now that molecular diagnostics is becoming more common worldwide. But even so, there is a large distance between the activity of the gene and its functional consequences, which are ultimately responsible for the symptoms and to which the drugs are directed. So the research team went further and looked at how mutations in these cancer-causing genes mechanically affect the inner workings of the cell. In the article, the researchers describe how the amount of protein in cancer cells rearranges the networks of protein-to-protein contacts, triggering cellular programs that promote cancer. In addition, mutations can affect important sites in a protein and suppress its ability to bind to each other or activate correctly, which also disrupts the formation of large protein networks. These results demonstrate the importance of proteomics in cancer research in understanding implications beyond mutations or epigenetic changes. The volume of data analyzed is so large that the team was able to study the far-reaching effects of the faulty proteins and go beyond their direct interaction. Many proteins play a role in various cellular systems, and their presence or absence can affect a wide range of cellular functions. Overall, mutations in many cancer-causing genes had very similar effects, suggesting that they condense into fewer cellular programs. However, other mutations have shown incompatible alternatives that could be used for therapeutic purposes in the future. Some of the tumors in the sample had more immune system infiltration than others. The researchers wondered if genetic changes in the factors that cause cancer could cause the production of aberrant proteins (neoantigens) capable of awakening the immune system. Their results confirmed a strong correlation between mutation and immune system infiltration, especially for some groups of very common cancer-causing proteins that may influence therapeutic pathways for patients with similar tumors.
The Ministry of Health joins the month of mental health promotion at the educational institution of Santa Juana de Lestonnac.
August 15, 2023
August 18, 2023