Researchers identify “mutational footprint” caused by chemotherapy that leads to side effects

Researchers at the Institute for Research in Biomedicine, Barcelona, have characterized the "mutational footprint" that occurs in cells as a result of chemotherapy and leads to long-term side effects.

The finding could help optimize cancer therapies so that side effects are minimized.

A team of researchers led by Núria López-Bigas, head of the Biomedical Genomics Laboratory at the institute, have identified the specific pattern of DNA mutations caused by six types of widely used therapies for cancer (one radiotherapy and five chemotherapy drugs).

The body acquires genetic mutations as part of the aging process

During the aging process, the body accumulates genetic changes. Most of these alterations are harmless, but in some cases, the mutations affect genes in a way that causes cancer to develop. The source of these mutations may be external to the body or "exogenous" such as tobacco smoke or UV radiation or the source may be "endogenous" and due to errors in how DNA is processed.

Chemotherapy has long-term side effects

Chemotherapy has revolutionized the treatment of cancer and enabled the survival of many patients. The drugs administered damage the DNA of cancer cells, making them unable to survive. However, the treatment also damages the DNA of healthy cells, which leads to long-term side effects.
First author of the current study, Oriol Pich, says it is important to remember that chemotherapies are highly efficient for the treatment of cancer.

But long-term side effects have also been reported in some patients. Studying the DNA mutations that occur in cells as a result of chemotherapies is the first step towards understanding the relationship between these mutations and the long-term side effects of these treatments."
Oriol Pich, first author

The team found the "mutational footprint" that leads to side effects

For the study, the Hartwig Medical Foundation provided Pich and colleagues with DNA sequences of metastatic tumors from around 3,500 cancer patients, along with information about the treatments they had been receiving.

As reported in the journal Nature Genetics, the researchers used bioinformatics techniques to characterize a specific pattern of mutations - the "mutational footprint" - that arose in tumors after treatment with some of the most widely used therapies.

"Once this 'footprint' has been identified, we can quantify the DNA mutations that have been caused by each kind of chemotherapy, as well as those caused by treatment combinations," says López-Bigas. "We have compared these numbers with the genetic alterations caused by natural endogenous processes."

López-Bigas says the team has calculated that, during treatment, some of these therapies cause DNA mutations at a rate that is between 100 and 1000 times faster than what normally occurs in a cell.

Optimizing cancer treatment in the future

The finding could be used to help optimize cancer treatments. López-Bigas says the aim is to maximize the beneficial effects of chemotherapies by killing cancerous cells while minimizing the mutation of healthy cells.

"This would be achieved through a careful combination of dose and treatment duration," concludes López-Bigas.

Genetic alterations caused by cancer therapies identified. Eurekalert. Available from: https://www.eurekalert.org/emb_releases/2019-11/ifri-gac111319.php