Cancer requires multiple changes in cellular properties, and the accumulation of the mutations that produce these changes can be accelerated.
A study published in the journal Nature and developed by a team of scientists from the Center for Systems Biology at Harvard University in Cambridge (USA) has concluded that genetic instability, an inherited increase in the rate of genetic mutation, accelerates evolutionary adaptation and is widespread in cancer.
Genetic instability is difficult to study in cancer, making it difficult to assess the evolutionary trajectories that inactivate both copies of a tumor suppressor gene and those that mutate only one of the two copies of a gene, exposing haploinsufficiency or predominantly altering the function of a protein.
In mammals, this genetic instability can arise from damage to the two copies of genes involved in DNA metabolism and cell cycle regulation or from the inactivation of one copy of a gene whose product is present in limited quantities (haploinsufficiency, basically when some genes express an abnormal phenotype); however, it has been difficult to determine the relative importance of these two mechanisms.
Human tumor genomes reveal mutations that are likely to cause genetic instability , but cannot easily reveal whether these mutations are homozygous or heterozygous.
To find out, the experts selected a more experimentally manageable organism, Escherichia coli (E.coli), a type of bacteria that lives in the gut. In this bacterium, the application of strong and repeated selection enriches the genetic instability. The scientists identified candidate, heterozygous mutations that cause instability.
“Engineering these mutations, as heterozygotes, in the ancestral diploid strain caused genetic instability. Mutations that inactivated a haploinsufficient gene copy were more common than those that dominant altered the function of the mutated gene copy. The mutated genes were enriched for genes that function in DNA transport, protein quality control and metabolism, and have revealed new targets for genetic instability, including essential genes , ”the authors explain.
Although only a minority (10 out of 57 genes) of the identified targets have homologous human genes implicated in cancer, the remainder are candidates to contribute to human genetic instability. To test this hypothesis, the experts inactivated six examples in a near-haploid human cell line: five of these mutations increased instability.
“We conclude that single genetic events cause genetic instability in diploid yeast cells and propose that similar and heterozygous mutations in mammalian homologues initiate genetic instability in cancer,” the authors comment.
What does genetic instability mean in cancer development?
“Genetic instability occurs when mutations and genomic changes occur more quickly; this is harmful because these mutations affect cancer guardian genes more often. This means that genetic instability contributes to starting the cancer genesis process, but also possibly to facilitating adaptation during metastasis and, surely, to cancer resistance to drugs when trying to treat it ” , Miguel Coelho, leader, explains of the study.
What implications will the findings of this study have?
“The study showing that one-hit mutations are enough to cause instability alerts us to the fact that cancer starts more often than we thought and by compromising cellular functions beyond DNA repair (such as normal metabolism and protein stability). More importantly, the study helps to understand why during cancer recurrence treatments fail: genetically unstable cells behave like “super-mutators” and adapt much faster to the drugs we use to try to control them (which leads to treatment failure and death) ”, continues Coelho.
What will be the next step in the investigation?
“ In the next step, I will develop evolutionary systems to understand other aspects of genetic instability, such as aneuploidy (the loss and gain of chromosomes) and we will conduct evolution experiments on organoids (assemblages of cells that mimic the environment of tissues and organs). and in live animal models. By better understanding what specific types of instability affect different types of cancer and how instability allows cancer to acquire resistance, we could design better treatment strategies that delay cancer progression, “concludes Coelho.
Referencia: Heterozygous mutations cause genetic instability in a yeast model of cancer evolution. Miguel C. Coelho, Ricardo M. Pinto & Andrew W. Murray. Nature (2019) . DOI: https://doi.org/10.1038/s41586-019-0887-y
