Genetic discovery could guide treatment for aggressive childhood cancer – Cancer Research UK

Specific genetic changes in tumors have been linked to how aggressive a rare childhood cancer will be, in a finding that scientists say could pave the way for new, tailor-made treatments.

The genetic changes found in rhabdomyosarcoma – a type of muscle cancer that mainly affects children – were also related to the patient’s age when the cancer developed and where it was found in the body. These factors influence how likely a child is to survive their illness.

This work is a fantastic example of how studying the underpinnings of childhood cancer can improve treatment choices.

– Sheona Scales, pediatric clinical trial leader at Cancer Research UK

Findings from this international study — the largest and most comprehensive on the disease to date — may lead some children to receive more tailored, intensive treatment, while others are spared aggressive interventions.

The study was led by The Institute of Cancer Research (ICR), funded in part by Cancer Research UK, and is published in the Journal of Clinical Oncology.

“Cancer in children is different from cancer in adults. At Cancer Research UK, we continue to invest in improving our understanding of childhood cancer to improve outcomes for our youngest cancer patients,” said Sheona Scales, head of pediatrics at Cancer Research UK.

A breakthrough study

The international team analyzed the DNA of 641 children and adolescents with rhabdomyosarcoma to look for changes related to, among other things, how quickly the cancer grew and how likely it was to respond to treatment.

Researchers looked at the two main disease subtypes separately – fusion gene positive and fusion gene negative.

The two main subtypes of rhabdomyosarcoma are fusion gene positive and fusion gene negative, depending on the presence of a so-called ‘fusion gene’. A fusion gene is formed from two previously separated genes, which can affect how the cell functions.

When looking specifically at children with fusion-negative rhabdomyosarcoma, researchers found that tumors with errors in two specific genes — MYOD1 and TP53 — did not respond as well to treatment. These errors were also linked to poorer survival.

Although the change in the TP53 gene was much rarer in children with fusion-positive rhabdomyosarcoma, it was still linked to poorer survival. This has led researchers to classify this genetic flaw in both groups as a “high risk” indicator.

Study leader Professor Janet Shipley, professor of molecular pathology at the ICR, said: “By looking at the genetic characteristics of different tumors, we can divide children into different risk groups to help guide their treatment.”

Researchers now plan to incorporate these new insights into the design of upcoming studies aimed at improving the management of the disease.

Learning from the past and looking to the future

In addition to uncovering new information, this study has called into question previous findings, including that the presence of a flaw in a gene called RAS is linked to poor outcomes.

However, researchers found that several RAS mutations appeared to be correlated with certain ages of onset of rhabdomyosarcoma. HRAS mutations arose in infants, KRAS mutations in toddlers, and NRAS mutations in adolescents.

Data shows that babies have worse survival rates than older children, possibly because doctors avoid more aggressive treatments such as radiation.

Thanks to the findings of this study, researchers now believe that using targeted drugs such as tipifarnib, which blocks HRAS, may be particularly beneficial for young, high-risk patients.

“Children with aggressive and difficult-to-treat cancers often undergo harsh treatments that can cause long-term side effects,” Scales says. “This work will hopefully lead to better outcomes for children with those cancers, not only in survival, but also in the impact their cancer treatment has on the rest of their lives.”

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