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New discoveries shed light on the genetic changes that underlie rare and aggressive childhood cancer

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New studies may lead to improved decision-making when allocating treatment to children with advanced cancer rhabdomyosarcoma after revealing the important genetic changes that underlie the development of the disease.

In the largest and most comprehensive study of rhabdomyosarcoma to date, scientists find that certain genetic changes in tumors are associated with aggression, early age of onset, and location within the body. Did.

All these factors affect a child’s chances of surviving the disease-and understanding how children are driven by the genetics of cancer is a new coordinating treatment for each patient. It can lead to a way.

Rhabdomyosarcoma is a rare type of cancer that resembles muscle tissue and mainly affects children. Less than 30 percent of children with rhabdomyosarcoma who have relapsed or have spread cancer will survive.

A new international study led by researchers at the London Cancer Institute may help find children with particularly aggressive cancers who require intensive treatment and close monitoring. You can also identify other children who can benefit from less aggressive treatment and escape some of the most serious side effects of treatment.

Researchers are already planning to incorporate new insights into the design of future clinical trials aimed at improving disease management.

An international group of researchers analyzed DNA from 641 patients with rhabdomyosarcoma.This study is today (Thursday) Journal of Clinical Oncology It was also funded by Cancer Research UK and several charities specially funded for the study of rhabdomyosarcoma, Chris Lucas Trust, Talan’s Trust and Alice’s Arc.

There are two major subtypes of rhabdomyosarcoma, depending on the presence of the “fusion gene”: fusion gene positive and fusion gene negative. A fusion gene is a hybrid gene formed from two previously separate genes (in this case, a gene called a PAX gene and a gene called FOXO1).

Looking at children with fusion-negative rhabdomyosarcoma, researchers found that children with tumor defects in the MYOD1 and TP53 genes were significantly less responsive to treatment and had poor survival outcomes. TP53 changed in 69 of 515 children and was associated with worse survival outcomes.

About half of the children who had the TP53 mutation in their cancer died of their illness, compared to one in four children who had the cancer without the TP53 mutation.

Researchers found mutations in MYOD1 in 17 of 515 children and linked them to both worse outcomes and the rapid progression of the disease. Findings suggest that children with these mutations may benefit from more aggressive treatment.

A small number of children with fusion-positive rhabdomyosarcoma (5 of 126) also had changes in TP53. None of these children survived cancer, and as a result, researchers also identified TP53 as a “high-risk” indicator for this subgroup.

Researchers also found that too many copies of the CDK4 or MYCN gene may be associated with poor outcomes of fusion-positive rhabdomyosarcoma, showing these genetic changes in 16 and 13 cases, respectively. I think it is. However, the number of cases in this study was small and needs further investigation in future studies.

New studies challenge the previous finding that the presence of defects in the RAS gene is associated with adverse consequences. However, researchers have found that some RAS mutations appear to correlate with a particular age of onset-HRAS mutations that occur in infants, KRAS mutations in infants, and NRAS in adolescence. Mutation.

Infants have previously been shown to have a lower survival rate than older children. This may be because clinicians avoid using more aggressive treatments such as radiation for the youngest patients. Taking into account the results of this study, researchers believe that the use of targeted drugs such as tipifarnib, which blocks HRAS, may be particularly beneficial to these young, vulnerable, and high-risk patients. I am.

Research leader Janet Shipley, a professor of molecular pathology at the Cancer Institute in London, said:

“Our findings shed light on the underlying genetic changes in rhabdomyosarcoma, a rare and aggressive childhood cancer. By examining the genetic characteristics of different tumors, different children It can be divided into various risk groups and can be used as a guideline for treatment.

“Decades of clinical trials have created the current complex system for assigning risk to children with rhabdomyosarcoma, but the current system is sufficient to properly assign treatment to individual children. It turns out to be inaccurate. Our findings need to improve the current system and the treatments offered by clinicians. Ultimately, further research reveals high levels with specific genetic defects. New drugs may be revealed to coordinate the treatment of patients with risk rhabdomyosarcoma. “

This international collaboration has linked certain genetic changes in cancer to the way children respond to treatment. It should help clinicians treat their children according to the specific characteristics of their cancer and their risk of developing their cancer. The findings are true not only for survival but also for quality of life by not only choosing the children in need of the most aggressive treatment, but also saving other children at low risk from the side effects of intensive intervention. May affect. “”

Professor Paul Workman, Chief Executive Officer, London Cancer Institute

Alice’s arc was inspired by Sarah and David’s daughter Alice, who was diagnosed with rhabdomyosarcoma at the age of three. Alice’s Arc was established shortly after her diagnosis. Alice died four and a half years later at the age of seven. Sara Wakeling, co-founder of Alice’s Arc, said:

“We believe that the future of effective and kind treatment of rhabdomyosarcoma depends on understanding the characteristics of each individual’s tumor and adjusting the treatment accordingly. We are pleased to have played a role in helping to better understand these genetic features and how they work. They are part of the prediction of outcomes and their impact on treatment pathways. With the ICR team. We look forward to working together to uncover the findings of more clinically translatable studies to defeat this devastating childhood cancer. “

Source:

Journal reference:

Sharne, JF, et al. (2021) Genomic classification and clinical outcome of rhabdomyosarcoma: Report from the International Consortium. Journal of Clinical Oncology. doi.org/10.1200/JCO.20.03060..

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