Chemotherapy suggests that healthy blood cells can “look old”

Some chemotherapeutic drugs cause more damage to healthy cells than others, new research finds.

Researchers have discovered four new mutation signatures related to chemotherapy – patterns of DNA damage left behind by certain classes of drugs. They also identified several drugs that can even “artificially aging” healthy blood cells through these mutations.

Findings released Tuesday (July 1) in Journal Nature Genetics could help doctors choose cancer treatments that cause minimal knock-on damage to patients’ bodies, scientists say.

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Some cancer chemotherapeutic drugs rapidly divide cells by damaging DNA and causing cell death. Cancer cells fit that description, but there are also healthy cells that divide quickly, such as those found in the bone marrow and blood. This new study aims to investigate how chemotherapy affects these healthy cells and do so in unprecedented detail.

The researchers compared blood from 23 people aged 3 to 80 years old, and were previously treated with chemotherapy in the blood of nine subjects with no history of cancer or chemotherapy. Collectively, people in the chemotherapy group received 21 treatments, including platinum and alkylating agents, which kill cancer cells by damaging DNA.

The team isolated blood stem cells and mature blood cells from the group. They extracted DNA from the cells and placed them in whole genome sequences. Mathematical models were used to identify many mutation signatures in the DNA of each cell. Four of these have never been reported in the space database of mutation signatures before and are suspected to be caused by chemotherapy.

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Some signatures were present in both cancer-free and chemotherapy samples, while 11 appeared only in the chemotherapy group. This included four new signatures.

Interestingly, however, not all drugs within the chemotherapy group caused the same degree of mutation burden. For example, the team found that cyclophosphamide, which is used to treat cancers such as multiple myeloma and breast cancer, causes much less mutations than others in its class.

A high number of mutations means there is a higher risk of developing another type of cancer after treatment called a secondary tumor. “The risk of secondary malignant tumors due to cyclophosphamide is known to be lower than that of other drugs in its class. He says that first research author, Dr. Emily Mitchell, is a hematologist and researcher at the Welcome Sanger Institute and a clinician at Cambridge University Hospital. That said, the risk is not zero.

Cancer is caused by mutations that lead to the growth of uncontrolled cells. However, genetic variation is also commonly associated with aging.

“Each cell in our body accumulates mutations over time in a certain way,” said Dr. Francesco Maura, a hematologist and researcher at Memorial Sloan Kettering Cancer Center in New York City, who was not involved in the study. When chemotherapy introduces mutations into blood cells, especially blood cells, “it doesn’t necessarily mean that stem cells are aging. You’re just having more mutations,” he said. These chemotherapy-induced mutations pose the same risks as age-related mutations, meaning their accumulation increases the risk of cancer.

Some study participants received chemotherapy that carried ten times the number of mutations in the blood than healthy, untreated children of his age. The infant’s blood cells looked older than the blood cells of an 80-year-old study participant who had never received chemotherapy. However, while the accumulation of mutations makes the cells look old, it does not always lead to tumor growth, just as not all people of age get cancer.

This study had limitations, including small sample sizes. Researchers acknowledged that studying blood in a test tube may have distorted the results because it does not completely replicate the human body’s environment. Mitchell said her group would like to perform similar experiments in a larger cohort and circulating blood, but there is no plan to do so anytime soon.

Mitchell pointed to the work of her and her colleagues, published in the Journal of Lancet Oncology in 2024 as an example of where this type of research goes. They demonstrated that alternative chemotherapy combinations for Hodgkin’s lymphoma and that they function similarly to standard options, with fewer knock-on mutations.

Although Hodgkin lymphoma has a sclerosis rate of over 80%, this approach can be more difficult to apply for other types of cancers with low cure rates. Furthermore, secondary tumors take years to develop, so people need to survive for a while to encounter the first treatment. Optimizing early chemotherapeutic drugs to minimize mutations is useless if cancer survival is not high.

In Maura’s words, “First, we must treat you [that type of] cancer. Next, we work to reduce the toxicity of the treatment. ”