King's College London

Researchers from King’s College London, in collaboration with the Wellcome Sanger Institute, the University of Cambridge and the Francis Crick Institute, set out to investigate the under-appreciated impact of platinum-based chemotherapy drugs on healthy tissues.

Platinum-based chemotherapies are drugs which contain the element platinum and are used to treat many different types of cancer. They are highly effective at treating a range of cancers in both adults and children. However, children who undergo cancer treatment can face long-term health problems, including secondary cancers and metabolic liver conditions. Understanding how chemotherapy affects healthy tissues is therefore critical to balancing the effectiveness of treatment with its potential long-term impacts.

The study, published in Science, found that while effectively destroying cancer cells, platinum-based chemotherapy can cause extensive DNA changes in healthy cells, with some treated children showing levels of DNA damage comparable to those found in adult tissues after decades of natural ageing.

In general, chemotherapy works by causing DNA damage in cancer cells, ultimately destroying them. Despite being a crucial tool in cancer treatment, this can also leave surviving healthy cells with patterns of DNA damage known as mutational signatures. While some of these signatures have been documented by previous research, their potential impact on long-term health is not always clear.

Recent advances in genomic sequencing technology have made it possible to detect previously hidden DNA changes. In this study, the team used a technique called NanoSeq to investigate the link between early-life chemotherapy treatment and DNA changes that persist later in life. NanoSeq is a highly accurate DNA sequencing method developed by scientists at the Wellcome Sanger Institute that can detect very low levels of DNA mutations.

The researchers analysed 186 blood samples, liver tumour samples and non-cancerous liver tissue from nine children, collected following treatment with platinum-based chemotherapy. The majority of the samples were collected at time of liver surgery at King’s College Hospital. An additional 30 samples from two children with liver cancer who had received non-platinum chemotherapy were also included.

The study further examined 47 samples from children with cancers other than liver cancer. These included samples from children who had received platinum-based chemotherapy, those who had received non-platinum treatment, and children who had not undergone cancer treatment.

The researchers identified distinctive and previously unseen patterns of DNA damage in the liver that appeared to be linked to platinum chemotherapy. This mutational signature was not found in any other tissues. Because this signature was specific to the liver, the researchers suggest it may be caused as the chemotherapy is broken down by the organ.

The analysis also revealed a much higher number of DNA changes across multiple tissues following platinum-based treatment. In some children, the number of genetic changes was comparable to levels seen in adult tissues. Some of these changes are considered potential cancer drivers, meaning they could increase the risk that cells develop into cancer. However, this complication of childhood cancer treatment is very rare.

Dr Foad Rouhani, Reader at King’s College London, Group Leader at the Francis Crick Institute and co-senior author, said: “Beyond its significance for children with cancer, our findings have unearthed something quite unprecedented about chemotherapy and DNA damage: The same chemotherapy drug caused different types of DNA damage across tissues. This is a fundamental observation that questions our assumption that chemotherapy causes the same DNA damage in all tissues."

Dr Anna Wenger, first author at the Wellcome Sanger Institute and the University of Gothenburg, said: “Our study represents a milestone in revealing the DNA damage that chemotherapy causes in normal tissues. We explored what this might mean for children who undergo this life-saving treatment at a young age, as delayed side effects from treatment often unfold over a lifetime. By using cuttings edge genomics, we revealed that certain chemotherapy drugs ‘age’ the children’s healthy cells, causing, in a short period, the same amount of DNA damage that would normally accumulate over decades and be seen in a middle-aged adult. Our finding enables us to begin to think about ways in which we could protect healthy tissues from DNA damage.”

Dr Ellie Waters-Barnes, patient advocate who was not included in this study, said: “As someone who is not only a recently qualified doctor but also a childhood cancer survivor, the potential impact of this research fills me with a lot of hope. Hope for a future where the drugs we use to treat children with cancer do not lead to lasting health problems and secondary malignancies. Hope that children can survive cancer without feeling the burden of the treatment for the rest of their lives.”

Professor Sam Behjati, co-senior author at the University of Cambridge and Director of the Cambridge Children’s Research Institute, formerly at the Wellcome Sanger Institute, said: “Chemotherapy is the key to curing cancer in children, and there is no alternative. At the same time, chemotherapy causes damage to normal tissues which can manifest as adverse effects in later life. Our work now reveals a plausible mechanism, DNA damage in normal tissues, through which chemotherapy in childhood may cause late adverse effects. The next step will be to gain a deeper understanding of this damage which may enable us to develop protective treatments to reduce long-term health risks for childhood cancer survivors.”

The researchers emphasise that chemotherapy remains a highly effective treatment for childhood cancer. Understanding its lasting effects on healthy tissues could help inform future research into ways of protecting healthy cells and reducing long-term side effects for childhood cancer survivors.