A genomic view of DNA damage in chemotherapy
Seventeen of 23 individuals exposed to chemotherapy had far more genetic mutations than could be explained by normal aging. Even more revealing was the discovery of eight unique mutational signatures that were found only in the chemotherapy group. While some of these fingerprints matched the known damage profiles of certain chemo drugs, four of them were entirely new to science, uncovering previously unknown ways these treatments can alter our DNA
Chemotherapy is one of modern medicine’s most powerful weapons against cancer. The concept of using chemical molecules to treat diseases came up in the 1900s with German scientist Paul Ehrlich using chemical “magic bullets” to target diseases — especially infections. He is also credited to have coined the term chemotherapy. The field truly blossomed in the mid-20th century with landmark discoveries of nitrogen mustard by Alfred Gilman and Louis Goodman from Yale University and the discovery of methotrexate by Sidney Farber and colleagues at Boston Children’s Hospital, which revolutionised the treatments for blood cancers.
For decades, the primary cancer treatments were surgery and radiation, but they shared a critical limitation: they only worked on tumours confined to a single area. They were often ineffective against cancer that had metastasized, or spread throughout the body.
Chemotherapy revolutionised treatment because it works systemically. The drugs are delivered into the bloodstream, allowing them to travel throughout the body and attack cancer cells wherever they are. This ability to fight widespread disease made chemotherapy a cornerstone of modern cancer care. When used in combination with surgery and radiation, it became the new standard, significantly increasing survival rates for many cancers, such as breast cancer.
Benefits come at a cost
This systemic approach comes at a cost. Chemotherapy drugs are designed to kill rapidly dividing cells, a hallmark of cancer. However, they also have additional effects on normal cells, the early effects of which manifest as toxicity or adverse events manifesting in different organs including nervous systems, kidney, blood, heart, and reproductive organs. This collateral damage is what causes the familiar short-term side effects, from nausea and hair loss to fatigue and organ damage. There have been multiple studies in the past which have suggested chemotherapy could have a long term and significant risk of developing cancers — including of the blood as well as organs such as kidney, lung, bladder and gastrointestinal tract.
This raises a crucial question: how exactly does chemotherapy inflict this long-term damage at the most fundamental level on our genome. A groundbreaking study from the Wellcome Sanger Institute in the United Kingdom and recently published in Nature has provided some of the clearest answers to date. The researchers sought to create a detailed map of the genetic damage caused by these life-saving drugs.
Turning to genome sequencing
One of the ways to evaluate the damage to DNA would be to sequence cells exposed to chemotherapy. The DNA damage could be evaluated by the number of genetic mutations as well as the pattern of changes. Or statistically significant clustering of specific types of mutations occurring across the three billion-odd bases in the human genome, which provides a fingerprint of the agent and can be summarised as a mutation signature. Researchers sequenced whole genomes from blood from 23 individuals who had a blood or solid organ cancer and had previous exposure to one or more chemotherapeutic agents. Age of the individuals varied widely — 3-80 years — and the time of exposure to sampling ranged from one month to six years. The genome sequence of the individuals who were exposed to chemotherapy was compared with a control group of nine individuals who never had any exposure to chemotherapy.
Genome sequencing and analysing mutations alone would not possibly be the right way to solve the issue here. This is because mutations do accumulate even in normal healthy individuals over time, a natural process contributed by errors introduced in every cell division. This is estimated to be around 18 new genetic variations every year and accumulates throughout the life of the individual. Further mutations only occur in a subset of cells, and therefore identifying the mutations and their presence in the proportion of cells becomes extremely important.
Solving the puzzle
To solve this puzzle, the researchers used a clever, multi-step approach. They started by going directly to the source of all blood cells: the stem cells in the bone marrow. Since sequencing blood cells would not be able to identify the proportion of cells having mutations, the researchers isolated stem cells from each of the people who had chemotherapy and cultured them into ninety colonies so they could get a much-detailed view at the historical genetic damage. Further a subset of individual hematopoietic stem cells was cultured to over 500 single cell-derived colonies and each were subjected to sequencing to get a very high-resolution view of the mutations. They further compared the DNA from patients who had received chemotherapy to that of healthy individuals of a similar age. To get an even fuller picture, they also sequenced specific types of mature immune cells circulating in the blood.
The results were clear. The vast majority of individuals exposed to chemotherapy — 17 out of 23 — had far more genetic mutations than could be explained by normal aging. Even more revealing was the discovery of eight unique mutational signatures — specific patterns of DNA damage — that were found only in the chemotherapy group. These signatures act like a fingerprint left behind by a chemical agent. While some of these fingerprints matched the known damage profiles of certain chemo drugs, four of them were entirely new to science, uncovering previously unknown ways these treatments can alter our DNA
Implications of the study
This research opens up a number of avenues. Firstly, using whole genome sequencing helps in quantify the DNA changes in blood stem cells and could provide unique opportunities to clinicians to decide on or select specific chemotherapeutic agents. For example, a high mutational signature was observed for carboplatin and cisplatin compared with oxaliplatin and this is of significance, since the agents belonging to the same class and are of similar efficacy are often used interchangeably in chemotherapy. Additionally, this insight could aid in the development of newer derivatives of existing chemotherapies with similar efficacy, but with smaller damage to DNA.
Researchers also suggest that some chemotherapy agents can make a person’s blood-making system age much faster. Children who have had some of the chemotherapeutic agents could have mutations which make their blood look like it belongs to a much older person. This premature aging might also increase their risk of developing a new cancer later in life.
In summary, this study sheds light on how chemotherapy, while targeting cancer, can also harm healthy cells. It’s crucial to remember that chemotherapy is a life-saving tool and remains essential for treating many cancers. That’s why it is so important for patients to stick with their recommended treatment plan. At the same time, this is exactly the kind of research we need. It helps scientists move toward the goal of creating smarter, safer cancer treatments for the future.
(AI tools were used to reorganise and rephrase sentences in the article)
