Causes, Risk Factors, and Prevention of Rhabdomyosarcoma

Gene changes that make the IGF2 gene overactive play an important role in tumor growth in embryonal rhabdomyosarcoma (ERMS). Changes to IGF2 are seen in other types of RMS as well. Research to find gene changes specific to ERMS is ongoing.

Gene changes that make the PAX genes overactive are an important part of many cases of ARMS. The PAX genes play a role in cell growth when muscle tissue is being formed before birth, but these genes usually turn off when they are no longer needed. When cells grow and divide, sometimes pieces of DNA can be swapped between two chromosomes, the long strands of DNA in each cell. This process, called a translocation, can move one of the PAX genes next to the FOXO1 gene, which keeps the PAX gene on. This leads to a gene change called a PAX/FOXO1 fusion and causes tumor growth.

Not all ARMS has the PAX/FOXO1 fusion gene. In fact, about 1 out of 5 cancers that look like ARMS under the microscope have been found not to have the PAX/FOXO1 fusion gene typically seen in ARMS. Doctors have found that fusion-negative ARMS acts more like ERMS, which generally requires less intense treatment and has a better outlook.

Gene changes define 3 subtypes of spindle cell/sclerosing type RMS and can help doctors anticipate a child’s outlook. For example, gene changes in VGLL2 and NCOA2 have been seen in infants less than 1 year of age and have very good outcomes. Older children may have RMS with gene changes in MYOD1 which is more difficult to treat.

Changes in several different genes are usually needed for normal cells to become cancer cells. Scientists have found some other gene changes that set some RMS cells apart from normal cells, but there are likely still others that have not been defined yet.

RMS is most common in children younger than 10, but it can also develop in teens and adults. It is slightly more common in boys than in girls.

Some people develop certain types of cancer because they have inherited changes in their DNA (genes) from their parents. Some rare inherited conditions increase the risk of RMS (and usually some other tumors as well):

• Members of families with Li-Fraumeni syndrome are more likely to develop sarcomas (including RMS), breast cancer, leukemia, and some other cancers.
• Children with Beckwith-Wiedemann syndrome (BWS) have a higher risk of developing some childhood cancers including RMS. Children with BWS are also at increased risk of Wilms tumor, a cancer of the kidney, and hepatoblastoma, a cancer of the liver.
• Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, causes tumors to grow on skin, nerves, and bones. People with NF1 have an increased risk of cancers like breast cancer, gastrointestinal tumors (GIST), and RMS.
• DICER1 syndrome is a condition associated with increased risk for cancer, most commonly a unique cancer of the lungs called pleuropulmonary blastoma. People with DICER1 gene changes are at higher risk of RMS in the urinary or reproductive organs.
• Costello syndrome is very rare. Children with this syndrome have high birth weights and larger heads but then fail to grow well. They also tend to have coarse facial features and loose skin. They are prone to develop RMS as well as some other cancers.
• Noonan syndrome is a condition in which children tend to be short, have heart defects, and can be slower than typical children in developing physical skills and learning things. They are also at higher risk for cancers like leukemia and RMS.

These conditions are rare and account for only a small number of RMS cases. But they suggest that the key to understanding RMS might come from studying genes and how they work in very early life to control cell growth and development.

Some studies have suggested that being exposed to x-rays before birth might be linked with an increased risk of RMS in young children. Parental use of drugs such as marijuana and cocaine has been suggested as a possible risk factor as well. But these studies were small, and more research is needed to see if these factors are truly linked to RMS.