Many cytotoxic chemotherapy agents have long-term biological consequences, including premature aging of the cell population structure of healthy blood, the results of a study of the genetic effects of chemotherapy showed. These findings published in Nature Genetics may help to guide future treatments with less harmful adverse effects or strategies for mitigating such toxicities.
“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,” said first author Emily Mitchell, FRCPath, a PhD student at the Wellcome Sanger Institute and Clinician at Cambridge University Hospitals. “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.”
Study Methods and Rationale
Although the effects of chemotherapeutics on cancer cells are known, their effects on normal tissues and blood are less well understood. As part of the Cancer Grand Challenges, researchers looked at the impact of chemotherapy on mutational burden and cell population structure of normal blood cells, as consistent mutation quantities across samples may provide a good baseline.
The study authors sequenced the blood cell genomes from 23 individuals (between the ages of 3 and 80) who were treated with a variety of chemotherapy regimens for various blood and solid cancers. Results were compared with genomic data from nine healthy participants who had never received chemotherapy.
Key Study Findings
The researchers found that substantial somatic mutation loads with characteristic mutational signatures were found in the patients who had been exposed to certain chemotherapies, but the effects depended on the drug and types of blood cells. For example, the 3-year-old patient with neuroblastoma had more mutations than found in the 80-year-old control participants.
They identified four new mutational signatures from chemotherapy-treated patients. Platinum agents were found to induce significantly more mutations than other types of chemotherapeutics, such as oxaliplatin.
Chemotherapy induced premature changes in the cell population structure of normal blood, which was compared with normal aging processes. For younger patients, this could increase their risk for secondary cancers later in life.
“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,” said co-lead author Jyoti Nangalia, PhD, a Group Leader in the Cancer, Ageing and Somatic Programme at the Wellcome Sanger Institute and a consultant hematologist at Cambridge University Hospitals. “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.”
“I believe that the results of this study hold implications for the way that chemotherapies are used to treat [patients with] cancer. 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,” concluded coauthor and Cancer Grand Challenges team lead Sir Mike Stratton, FMedSci FRS, Senior Group Leader, Wellcome Sanger Institute.
Disclosure: For full disclosures of the study authors, visit nature.com.