The cells of the organism change throughout a person’s life. In most cases, these changes are harmless because they respond to a programmed mechanism of cell multiplication and cell death, which happens in an orderly manner. However, some genetic alterations can occur that cause cells to ignore these commands and begin to multiply in an aberrant manner, resulting in cancer. Tumours can occur as a result of alterations in the epigenome, caused by internal factors, by an error in DNA processing; or external factors, such as solar radiation, tobacco smoke, or some toxic substances.
A team of researchers at the Institute for Research in Biomedicine (IRB Barcelona), have determined the genetic alterations that cause six therapies used in cancer treatment: five chemotherapy and one radiotherapy.
Chemotherapy works by damaging the DNA of the cancer cells in order to kill them. The downside is that it can also kill off healthy cells. Nevertheless, this treatment has managed to ensure that a significant number of cancer patients survive. In this sense, Oriol Pich, a predoctoral student at IRB Barcelona published in Nature Genetics emphasizes that "It is important to note that chemotherapies are very effective in the treatment of cancer". "However, long-term side effects have also been described in some patients. Studying the mutations produced by chemotherapies in the DNA of patients' cells is a first step towards understanding the relationship of these mutations to the long-term side effects of these therapies".
Searching for the mutational fingerprint
To conduct the study, researchers obtained the sequence of the genomes of metastatic tumours of more than 3,500 patients, as well as information on the treatments that they received. Using bioinformatics, they were able to identify for each of the most common cancer treatments a specific pattern in the mutations of the patients' cells, i.e. a "mutational fingerprint" of the therapies.
"Once this "fingerprint" has been identified, we can quantify the mutations produced by each chemotherapy in the patients' DNA, as well as those produced by combinations of treatments," explains López-Bigas. "We have compared this measure with the genetic alterations due to natural endogenous processes in the cells. We have calculated that during the treatment time some of these chemotherapies cause alterations in the DNA at a rate between one hundred and one thousand times faster than we would expect in a cell".
The aim of the study is to improve the treatments used today to fight cancer.
López-Bigas sets as a goal to take advantage of the potential of chemo to destroy tumour cells while minimizing the number of mutations induced in healthy cells. "This would be achieved through a balanced combination of dose and duration of treatment," he says.
En busca de la huella mutacional
The study has been funded by the European Research Council, the Ministry of Science, Innovation and Universities and the Catalan Department of Enterprise and Knowledge. Oriol Pich has a grant from the Barcelona Institute of Science and Technology (BIST).
Source: Oriol Pich, Ferran Muiños, Martijn Paul Lolkema, Neeltje Steeghs, Abel Gonzalez- Perez and Nuria Lopez-Bigas. The mutational footprints of cancer therapies. Nature Genetics (2019). DOI: s41588-019-0525-5.