Life-saving chemotherapy treatment can have a hidden impact on the liver later in life, so researchers are investigating how to protect healthy tissues.
Histopathology image of liver tissue after chemotherapy treatment. Credit: Tissue Regeneration and Clonal Evolution Laboratory.
Children who undergo cancer treatment often face long-term health issues, such as liver conditions. Understanding why this happens, and potentially how to mitigate it, is a new research focus for surgeon scientist Foad Rouhani, who leads the Crick’s Tissue Regeneration and Clonal Evolution Laboratory.
“We’re interested in an organ’s ability to regenerate,” says Foad, who is also honorary consultant transplant surgeon at King’s College Hospital and Reader at King’s College London. “Specifically, we focus on the liver, as it can regrow at a remarkable rate, even if up to 70% has been surgically removed. Because children who have had chemotherapy can go on to develop liver conditions in later years, we think there might be a link between the liver’s extraordinary regeneration capability and the risk of developing mutations with time and with certain treatments.”
The lab’s interest in this research question stemmed from a collaboration with researchers at the Wellcome Sanger Institute and the University of Cambridge. In research published today in Science, the multidisciplinary team found distinctive DNA changes in the liver, a potential biological explanation for why childhood cancer survivors can face health issues later in life.
“Chemotherapy is the key to curing cancer in children, and there is no alternative,” says Sam Behjati, co-senior author and Director of the Cambridge Children’s Research Institute. “At the same time, chemotherapy causes damage to normal tissues which can manifest as adverse effects in later life.”
Chemotherapy works by causing DNA damage in cancer cells to kill them. It’s not surprising that a treatment as powerful as this can leave surviving healthy cells with patterns of DNA damage, known as mutational signatures. Some of these mutational signatures have been documented by previous research, but their impact on health is not always clear.
In the new study, published in Science, the team 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.
The samples were analysed using a genomic sequencing method called NanoSeq. This 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 as can be seen in adult tissues. Some of the DNA changes were found in genes typically associated with cancers, which may increase the risk that these cells may eventually develop into cancer. Thankfully this long term complication of childhood cancer treatment is very rare.
“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,” explains Anna Wenger, first author and postdoctoral researcher at the Wellcome Sanger Institute and the University of Gothenburg.
The study also demonstrated that the previously unseen pattern of genetic changes was specific to liver, and not to other tissues which have been equally exposed to platinum chemotherapy. This liver-specific pattern of mutational signatures – in the context of a body-wide systemic exposure to chemotherapy – was novel and completely unexpected. The team are now exploring whether the reason for this difference is that the chemotherapy is broken down differently in liver cells compared to other tissues in the body.
“Our work now reveals a plausible mechanism, DNA damage in normal tissues, through which chemotherapy in childhood may cause late adverse effects,” concludes Sam. “The next step will be to gain a deeper understanding of this damage which may enable us to develop protective treatments to reduce the long-term health risks for childhood cancer survivors.”
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.”
Foad is now looking into the mechanism behind the mutational signature in the liver. “We’re going to investigate why the liver is unique in this way,” he says. “Perhaps the way the liver can regenerate leaves it vulnerable to DNA changes after cancer treatment. Unlocking this could help us discover adjuvant therapies that successfully target tumours but which negate the effects of chemotherapy on the healthy liver.”
