The amount of DNA damage caused by certain chemotherapies used to effectively treat childhood cancer has been revealed, along with a hidden impact on the liver, paving the way for future research into new ways to mitigate these impacts.
Platinum-based chemotherapy drugs are powerful at treating cancer but can have an under-appreciated impact on the rest of the body. To investigate this, a team at the Wellcome Sanger Institute, the University of Cambridge, the Francis Crick Institute, and King's College London used new sequencing technologies and found distinctive DNA damage in the liver. They suggest that further research could lead to new ways to protect against this.
Published today (10 September) in Science, the researchers also discovered that while destroying cancer cells effectively, chemotherapy can 'age' a child's healthy cells. This results in children's healthy cells having the same amount of DNA changes that adult cells gain over many decades. This study provides a plausible direct link and biological explanation for why childhood cancer survivors often face health issues in later life, such as secondary cancers or liver disease.
The goal of this research is not to discourage the use of chemotherapy, which remains essential for curing childhood cancer. Instead, by identifying exactly how these drugs genetically damage healthy tissues, scientists hope to develop new ways to mitigate or prevent these DNA changes in the future, ultimately reducing the long-term health risks for survivors.
In general, chemotherapy works by causing DNA damage in cancer cells, ultimately destroying them1. Despite being a crucial tool, this can leave surviving healthy cells with patterns of DNA damage, known as mutational signatures. While some of these mutational signatures have been documented by previous research, their possible impact on health has not always been clear.
Platinum-based chemotherapies are effective at treating a range of cancers in both adults and children. As children who undergo cancer treatment often face long-term health issues as they reach adulthood, understanding the impact of treatment on their bodies is critical to ensure effective and balanced care.
Recent developments in genomic sequencing technology have started to reveal previously hidden DNA changes in childhood cancer. In this new study, the team used a technique called NanoSeq2 to identify the link between early-life chemotherapy treatment and the impacts that appear later in life.
This research analysed a total of 186 blood samples, liver tumour samples, and non-cancerous liver tissue from nine children, collected following treatment with platinum-based chemotherapy. An additional 30 samples from two children with liver cancer who had received non-platinum treatment were also included. The study further examined 47 samples from children with cancer other than liver cancer who had received platinum-based chemotherapy, those who had received non-platinum treatment, and samples from children who had not undergone treatment at all.
NanoSeq analysis revealed a much higher number of DNA changes in cells throughout multiple tissues after platinum-based treatment, with some children having the same number of genetic changes seen in adult tissues. Some of the DNA changes are considered cancer drivers, which may increase the risk that these cells will develop into cancer. This complication of childhood cancer treatment is very rare.
The study also revealed a previously unseen pattern of genetic changes in liver tissues. This did not appear in any other tissues and appeared to be linked to platinum-based chemotherapy. As it was only found in the liver, the team suggests that it might be caused during the breakdown of the chemotherapy treatment, which takes place in this organ.
The increased number of mutations in children's healthy cells along with the additional DNA damage seen in the liver could provide a plausible biological explanation as to why childhood cancer survivors face secondary cancers and other health conditions that are often described as 'premature ageing' health issues. Chemotherapy is an effective treatment against cancer, and understanding the lasting impact could help guide future research to find new ways to protect against this.
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' 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 middle-aged adults. Our finding enables us to begin to think about ways in which we could protect healthy tissues from DNA damage."
Dr Foad Rouhani, co-senior author at the Francis Crick Institute and King's College London, said: "Beyond its significance for children with cancer, our findings have unearthed something quite unprecedented about chemotherapy and DNA damage: The same chemotherapy drug can cause 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. In the case of the liver, we have seen that chemotherapy can cause distinctive DNA damage which may plausibly be the contributor to liver disease in adult life in these patients."
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."
