Cancer genome: from private to general
Common mutations were selected for different types of cancer
Kirill Stasevich, CompulentaCancer, as everyone remembers, begins with mutations, with violations of the DNA sequence, after which the cell begins uncontrolled division.
However, there are a great many types of cancer, and each has specific mutations that only distinguish it. And there are mutations that, on the contrary, turn out to be more or less universal and occur in many tumors. In addition, there are just mutations that may be harmful, but they have nothing to do with cancer.
Scientists have been trying for a long time to understand this mutational chaos of malignant tumors, to learn to distinguish one mutation from another. Not so long ago, a group of researchers from the Broad Institute (USA) realized how to distinguish oncogenic mutations from ordinary ones; with the help of an algorithm created by it, it is possible, for example, to obtain individual mutation passports for different tumors. And now the same team of Ged Getz, Matthew Meyerson and their colleagues reports in Nature Genetics that they have managed to solve another problem, that is, to find out what mutations that can be called pan-oncogenic, occurring in most cancerous tumors, should look like.
Scientists analyzed deletions and doubling of DNA sections in somatic cells, after which somatic cells get out of control. In their hands were about 5 thousand samples from 12 types of cancer, among which were tumors of the bladder, breast, colon, etc. It turned out that oncogenic deletions and duplications occur most often after a complete doubling of the genome, when a cell, due to some molecular error, receives not two chromosomes of each species, but four. In 37% of cases, such a doubling is followed by a malignant degeneration of the cell, and scientists were able at the same time to determine the genes on which such a doubling of the genome depends or not.
The second thing that the authors noticed: oncogenic mutations inside the chromosome look somewhat different than those that occur at the chromosomal ends, or telomeres: telomeric mutations capture large fragments of DNA. From this, the authors conclude that the mutation mechanisms also differ in where these mutations occur.
Further, it turned out that there are 140 sites in the genome where mutations are most likely to lead to cancer. At the same time, the researchers emphasize that a specific set of mutant zones from these 140 may change in each individual case. Among the genes that are located in them, only 35 have so far been known as known oncogenes, with respect to the rest, scientists obviously have a long and painstaking work to do.
The most frequently recurring foci of somatic changes in the number of copies of genes.
Figure from the article by Zack et al. Pan-cancer patterns of somatic copy number alteration – VM
Finally, the action of many of the same 140 oncogenic zones is controlled by epigenetic mechanisms that determine how a particular DNA fragment is packaged or, conversely, accessible to molecular machines that read information from it. That is, oncogenic mutations, therefore, interfere with the work of epigenetic regulators.
It is worth emphasizing once again that the authors attribute all of the above to mutations that can be found, if not in all, then in the vast majority of cancers. Based on these signs, it is possible to compile a database of cancer mutations, separating private, individual mutations from general ones. In addition, they can detect some parts of the genome, individual genes whose possible involvement in the development of cancer has not yet been studied.
Ultimately, this should lead to the creation of more effective treatments that will take into account, for example, not only the genetic effect of the mutation, but also its impact on epigenetic processes.
Prepared based on the materials of the Broad Institute: Study finds rules for cancer drivers.
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