International study of rare childhood cancer finds genetic clues, potential for tailored therapy

STATUE: New findings suggest that children with rhabdomyosarcoma may benefit from tumorigenic research. view more

Credit: National Human Genome Research Institute

In children with rhabdomyosarcoma or RMS, a rare cancer that affects muscles and other soft tissues, the presence of mutations in several genes, including TP53, MYOD1, and CDKN2A, appears to be associated with a more aggressive form of the disease and a smaller size. survival rate. This finding comes from the largest international study ever on RMS, led by scientists at the National Cancer Institute’s (NCI) Center for Cancer Research, part of the National Institutes of Health.

The study, published in the Journal of Clinical Oncology on June 24, provides an unprecedented look at data for a large cohort of patients with RMS, and provides genetic clues that could lead to more widespread use of genetic tumor testing to predict how individual tumors are. patients with this childhood cancer will respond to therapy and to the development of targeted treatments for the disease.

“These discoveries change what we do with these patients and lead to a lot of really important research into developing new therapies that target these mutations,” said Javed Khan, MD, of NCI’s Genetics Branch, who led the research.

“The standard therapy for RMS has been chemotherapy, radiation therapy, and surgery for nearly a year. These children receive many toxic treatments,” said the study’s lead author, Jack Shern, MD, of NCI’s Pediatric Oncology Branch. “If we could predict who will do well and who won’t, then we can really start tweaking our therapies or eliminating therapies that aren’t going to be effective in a particular patient. And for the kids that aren’t going to Well, this allows us to think about new ways to treat them.”

RMS is the most common type of soft tissue sarcoma in children. In patients whose cancer has remained localized, meaning it has not spread, combination chemotherapy has resulted in a five-year survival rate of 70%-80%. But in patients whose cancer has spread or has come back after treatment, the five-year survival rate remains low at less than 30%, even with aggressive treatment.

Physicians have typically used clinical features, such as the tumor’s location in the body, as well as its size and extent to which it has spread, to predict how patients will respond to treatment, but this approach is inaccurate. More recently, scientists have found that the presence of the PAX-FOXO1 fusion gene found in some patients with RMS is associated with poorer survival. Patients are now being screened for this genetic risk factor to help determine how aggressive their treatment should be.

Scientists have also begun to use genetic analysis to dig deeper into the molecular workings of RMS in search of other genetic markers of poorer survival. In this new study – the largest effort to profile RMS tumors in genomic profiling to date – scientists from NCI and the Institute for Cancer Research in the United Kingdom analyzed DNA from tumor samples from 641 children with RMS who were treated over a period of time. of two decades in various clinical trials. Scientists looked for genetic mutations and other abnormalities in genes previously associated with RMS and linked that information to clinical results. Of the patterns that emerged, patients with mutations in the tumor suppressor genes TP53, MYOD1, or CDKN2A had a worse prognosis than patients without those mutations.

Using next-generation sequencing, researchers found a median of one mutation per tumor. Patients with two or more mutations per tumor had even worse survival outcomes. In patients without the PAX-FOXO1 fusion gene, more than 50% had mutations in the RAS pathway genes, although RAS mutations did not appear to be associated with survival outcomes in this study.

The researchers believe that while they have identified the key mutations that may stimulate RMS development or provide information about prognosis, they have only scratched the surface in defining the genetics of this cancer, with many more mutations to be found. that have yet to be discovered. They note that more work is needed to identify targeted drugs for those mutations, and future clinical trials could incorporate genetic markers to more accurately classify patients into treatment groups. Two NCI-sponsored clinical trials from the Children’s Oncology Group are currently being developed using these markers, and all participants will have their tumors molecularly profiled.

The researchers hope that routine genetic testing of tumors for rare cancers, such as RMS, will soon become a standard part of the treatment plan, as it is for more common cancers, such as breast cancer.

“Genetic testing will become standard of care,” said Dr. Shern. “Instead of just the pathologists looking at these tumors, we’re now going to have molecular profiling, and that’s a leap forward.”


This study was conducted by an international consortium consisting of scientists from the NCI and the Children’s Oncology Group in the United States, and the Children’s Cancer and Leukemia Group and the Young Onset Soft Tissue Sarcoma Subgroup of the National Cancer Research Institute in the United Kingdom. The data is available at The research was supported by NCI and St. Baldrick’s Foundation in Monrovia, California.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and the NIH’s efforts to dramatically reduce cancer prevalence and improve the lives of cancer patients and their families through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, visit the NCI website at or call the NCI Contact Center, the Cancer Information Service, at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the national medical research agency, includes 27 institutes and centers and is part of the United States Department of Health and Human Services. NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of any press releases posted on EurekAlert! by sponsoring institutions or for the use of information through the EurekAlert system.

Comments are closed.