New insights on genetic damage of some chemotherapies could guide future treatments with less harmful side effects

For the first time, scientists have systematically studied the genetic effects of chemotherapy on healthy tissues.

Researchers from the Wellcome Sanger Institute, the University of Cambridge, Cambridge University Hospitals NHS Foundation Trust (CUH) and their collaborators analyzed blood cell genomes from 23 patients of all ages who had been treated with a range of chemotherapies.

Published in Nature Genetics, the researchers show that many but not all chemotherapy agents cause mutations and premature aging in healthy blood.

As part of the Cancer Grand Challenges team Mutographs, the researchers uncovered new patterns of DNA damage, or mutational signatures, associated with specific chemotherapy drugs.

The researchers suggest that the damaging genetic effects of chemotherapy identified by whole genome sequencing could guide the future treatment of patients with effective chemotherapies that have less harmful effects on healthy tissues.

Chemotherapy is a type of anti-cancer treatment that works by killing cancer cells. It is a systemic treatment, meaning it works throughout the body, and can be administered as a single chemotherapy drug or a combination of drugs. In developed countries, it is estimated that around 10% of the population has received chemotherapy treatments for cancer and other diseases at some point in their lifetime.

Chemotherapy can have long-term side effects on healthy, non-cancerous tissues, and is associated with an increased risk of secondary cancers. However, there is limited understanding of the biological mechanisms underlying these side effects.

With new genomic technologies, researchers can explore mutations in normal cells and begin to investigate the extent and long-term consequences of DNA damage from chemotherapy on healthy tissues.

In a new study, scientists set out to research the effects of chemotherapy on healthy blood. The Mutographs team at the Sanger Institute, University of Cambridge, CUH and their collaborators chose to study blood due to its ease in sampling and ability to culture blood in the laboratory.

Plus, the numbers of mutations in normal blood are very consistent between people, giving a good baseline to see whether they are higher in individuals who have received chemotherapy.

The researchers sequenced blood cell genomes from 23 individuals aged three to 80 years, who had been treated with a range of chemotherapies for various blood and solid cancers. Most of the patients were treated at Addenbrooke’s Hospital in Cambridge and had received a combination of chemotherapy drugs.

Collectively, they had been exposed to 21 drugs from all of the main chemotherapy classes, including alkylating agents, platinum agents and anti-metabolites. The results were compared with genomic data from nine healthy people who had never received chemotherapy.

From analyzing the whole genome sequence data, the team found that many classes of chemotherapeutics, but not all, do produce higher numbers of mutations in normal blood cells. For example, a three-year-old patient who was treated for neuroblastoma, a cancer of nerve tissue, had more than the number of mutations found in 80-year-olds who had never received chemotherapy.

By looking at patterns of damage in the DNA, known as mutational signatures, the researchers showed that different chemotherapeutics have different mutational signatures, and identified four new signatures found in chemotherapy-treated patients.

For instance, the researchers found that some platinum agents, such as carboplatin and cisplatin, caused very high numbers of mutations. Whereas other drugs in the same class, such as oxaliplatin, did not.

The researchers suggest that if these drugs are used interchangeably in cancer treatment, and assuming they have the same effectiveness, then this sort of genetic information could be incorporated in order to administer chemotherapies with fewer harmful effects.

The team also made discoveries around the effects of chemotherapy on the population of cells that generate blood, known as hematopoietic stem cells.

In normal aging, the hematopoietic stem cells producing blood decrease in diversity, due to the expansion of clones of cells that have “driver” mutations in cancer genes. Chemotherapy caused a similar pattern of change, but prematurely in some middle-aged adults. Particularly in children who have had chemotherapy, their blood appeared to prematurely age, which may increase the risk of secondary cancer later in life.

Scientists suggest that genomic data could help in choosing the chemotherapies for children that minimize this premature aging, and genomic technologies could monitor for further changes later in life.

Dr. Emily Mitchell, first author at the Wellcome Sanger Institute and clinician at CUH, said, “For the first time, we have taken a systematic view of the genetic effects of chemotherapy on healthy tissues—in this case, blood. We find that some, but not all chemotherapies cause genetic mutations and premature aging in normal blood.

“This study lays the groundwork for future research into the effects of chemotherapy on many other normal tissues, including multiple tissue sampling pre and post-treatment, across a range of chemotherapies in a larger group of patients. This comprehensive view would reveal the full range of effects of different chemotherapies, and help us to optimize patient health in the long term.”

Dr. Jyoti Nangalia, co-lead author at the Wellcome Sanger Institute and Consultant Hematologist at CUH, said, “The effects of chemotherapy we see here—increasing numbers of mutations and premature aging of healthy blood—reasonably contribute to the heightened risk of additional cancers and the patient’s ability to tolerate further treatments in the future.

“Given that for many cancers, chemotherapy drugs can be switched with other agents to achieve similar results, we hope such genomic data will guide the optimization of future treatment plans to deliver effective chemotherapies with much fewer damaging side effects for patients.”

David Scott, Director of Cancer Grand Challenges, said, “This important research helps us better understand how some chemotherapy drugs can affect healthy cells as well as cancer cells.

“While many cancers can now be targeted using precision therapies, chemotherapy remains a key way to treat some cancers and saves many lives every year, so it’s vital that patients continue with the treatment recommended by their doctor. At the same time, studies like this are crucial for helping scientists improve cancer treatments in the future—making them not only more effective but also safer for people living with cancer.”

Professor Sir Mike Stratton, Mutographs team lead and co-lead author at the Wellcome Sanger Institute, said, “I believe that the results of this study hold implications for the way that chemotherapies are used to treat cancer patients. We are constantly on the lookout for better ways of giving therapy and minimizing the side effects of toxic, systemic treatments.

“I’m hopeful that the genomic information from this and future studies will guide choices of chemotherapies, and their adoption in clinical practice.”