Why does this or that mutation sometimes cause cancer, and sometimes not? Researchers from the CNIO, the CRG and the IRB Barcelona have just discovered one of the reasons
IRB/DICYT The language in which the DNA book of life is written is still being deciphered, and so it remains a challenge to translate what genes say into physical traits in the body. For example, why does this or that mutation sometimes cause cancer, and sometimes not? Researchers from the CNIO, the CRG and the IRB Barcelona have just discovered one of the reasons: the power of a mutation depends on its interaction with another, and often even on the relationship between that pair of mutations with a third one.
It is the first time that the existence of these third-order interactions has been demonstrated in cancer. His finding is equivalent to revealing one of the grammatical rules in which genetic language is; It goes on to say – continuing with the metaphor of writing – that the same word (mutation) has different meanings depending on what other words accompany it in the sentence, and the context in which it appears.
The work is led by Dr. Solip Park, Head of the Computational Genomics of Cancer Group at the CNIO, Dr. Ben Lehner, ICREA researcher and Coordinator of the Biological Systems Program of the CRG (Center for Genomic Regulation) and Dr. Fran Supek, ICREA researcher and head of the Genome Data Science laboratory at IRB Barcelona (Institute for Biomedical Research), and it has just been published in the journal Nature Communications.
As stated by Dr. Park, “it is the first in-depth systematic analysis, and with multiple data, of the interactions between genetic alterations implicated in cancer. There are several studies that study a single gene or a single type of cancer, but this is the first systematic on a large scale ”.
Medium-term clinical implications
The research opens a way to decipher the functioning of the half thousand mutations known to be involved in cancer. If successful, the clinical implications would be important. Genetic diagnosis would be more precise and new therapeutic targets could be sought, since the best way to counteract a certain mutation could be by acting on another.
“Until now, research has usually focused on alterations in a single gene to act on with drugs, but this approach implies that the associations between different genes involved in cancer must be considered,” explains Dr. Park.
Data from 10,000 tumors
For years, those who research cancer genetics have known that this disease results, in the vast majority of cases, from different genetic alterations acting at the same time. But only now, with big data techniques and great computational power, has it been possible to tackle the challenge of deciphering these interaction networks.
The authors of the work, computational biologists, turned to the Cancer Genome Atlas (TCGA). They analyzed the interactions between the genetic alterations present in 10,000 human tumors of some thirty different types, affecting more than 200 genes.
The hypothesis about how cancer genes are activated is not correct
By analyzing the interactions between genetic alterations, and finding a third level in the network, the authors dismantle one of the most accepted hypotheses about how genes that promote tumor development are activated. It is the so-called two-hit model -two hit model in English-.
An oncogene promotes cancer when it is activated, while a tumor suppressor gene works the other way around, it is its inactivation that drives cancer. “The classical theory – explains Dr. Park – is that a single mutation in an oncogene can be enough to promote cancer, while for a tumor suppressor gene to act, the inactivation of both copies of the gene, the father’s and the mother’s. It is the hypothesis of ‘the two blows’. But many exceptions to this classic model are coming to light, and this work finds an explanation ”.
His analysis of the networks of interactions between the genetic alterations of 10,000 tumors reveals that many genes implicated in cancer, be they oncogenes or tumor suppressor genes, may take a hit or two depending on what other mutations are at work.
Cancer is reached in several ways
“The correct genetic blueprint for a gene therefore depends on the other mutations in the genome,” write Drs. Park, Lehner and Supek. “A second hit in the same gene, or an alteration in a different gene in the same pathway, represent alternative evolutionary pathways to cancer.”
In other words, we must not only take into account the effects of individual mutations or interactions in pairs, but also what happens when three or more alterations are combined ”, adds Dr. Park. The researchers postulate that this new grammatical rule of genetic language is universal, that is, it is not only involved in cancer.
“It is likely that these principles of genetic architecture apply to other diseases as well. We believe that systematically analyzing higher-order genetic interactions can also help to understand the molecular mechanisms that cause other human diseases, ”the authors note.
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