Researchers at Memorial Sloan Kettering have discovered a gene mutation that may explain why a subset of patients with rhabdomyosarcoma — a rare cancer that affects mainly children and young adults — have a particularly aggressive form of the disease that responds poorly to standard treatments such as chemotherapy.
The results, reported recently in Nature Genetics, could guide physicians in tailoring treatments and could also lead to the development of new drugs for the disease.
What Is Rhabdomyosarcoma?
Rhabdomyosarcoma arises in cells that form skeletal muscle and usually affects children five or younger. Less commonly, it is diagnosed in older children and young adults. The condition is a type of soft tissue sarcoma, a group of more than 70 rare cancers that originate in soft tissues such as fat, muscles, nerves, and tendons.
“Because there are so many subtypes of soft tissue sarcoma, and each person’s disease differs in its behavior and genetic makeup, some of these cancers tend to be very difficult to diagnose and treat,” says molecular pathologist Marc Ladanyi. He led the study, which is part of an extensive MSK effort to determine the gene changes that drive distinct sarcoma subtypes.
How the Study Was Done
The researchers analyzed 20 rhabdomyosarcoma tumors by whole-exome sequencing, a method of obtaining comprehensive blueprints of DNA changes in tumors by analyzing all parts of the genome that code for protein. The tumor samples had been taken from patients with the two most common subtypes of the disease — embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma — who had been treated at MSK. The age of these patients varied from one to 25 years.
A Striking Finding
As the researchers surveyed information about the thousands of genes in these tumors, one finding particularly grabbed their attention: Two of the 11 ERMS tumors analyzed had the exact same mutation in a gene called MYOD1, which had not previously been linked to the disease.
“Remarkably, research done more than two decades ago had shown that this mutation interferes with the development of skeletal muscle cells,” Dr. Ladanyi says. “Immature muscle cells that have the mutation proliferate uncontrollably instead of maturing into normal muscle cells.”
An Aggressive ERMS Subtype
The researchers analyzed tumor samples from an additional 93 ERMS patients to specifically look for the MYOD1 alteration. Overall, it was present in almost one tumor out of ten. The prevalence of the mutation was higher among tumors in teenagers and young adults, and less frequent among small children and infants.
“We noticed that the teenagers and young adults whose tumors had the mutation did very poorly compared to others with ERMS,” Dr. Ladanyi says. “This finding is immediately helpful to pediatric oncologists because it gives them a new way to identify those patients who might need more intensive treatment.”
In addition, the researchers analyzed 25 alveolar rhabdomyosarcoma samples and did not detect the mutation in any of these tumors, suggesting that it occurs mainly in ERMS.
How the Research Moves Forward
In Dr. Ladanyi’s lab, researchers are now conducting large-scale screens of ERMS tumors that carry the MYOD1 mutation to find new therapies that could be especially effective against these difficult-to-treat cancers.
In the current study, the researchers noted that half of the tumors that had the MYOD1 mutation also had gene changes that affect a cellular process called the AKT pathway — an indication that ERMS tumors with the MYOD1 mutation might be sensitive to a family of drugs called PI3 kinase inhibitors.
“This gives us hope that patients with this subtype of the disease for whom standard treatments often fail potentially could benefit from targeted therapy in the future,” Dr. Ladanyi explains. “However, more research is needed to understand what types of drugs individual patients might benefit from.”