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The cause of most cases of rhabdomyosarcoma (RMS) is not well understood, and there are very few known risk factors for this type of cancer. But researchers are learning how normal cells become cancerous because of certain changes in their DNA.

DNA is the chemical in each of our cells that makes up our genes, which control how our cells function. Genes are packaged in chromosomes (long strands of DNA in each cell). We normally have 23 pairs of chromosomes in each cell (one set of chromosomes comes from each parent). We usually look like our parents because they are the source of our DNA. But DNA affects more than how we look.

Some genes control when our cells grow, divide into new cells, and die:

• Genes that help cells grow, divide, or stay alive are called oncogenes.
• Genes that slow down cell division or make cells die at the right time are called tumor suppressor genes.

Cancers can be caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes.

Gene changes affecting RMS

A small portion of people with RMS have inherited gene changes from a parent that put them at higher risk. For example, people with Li-Fraumeni syndrome have changes in the TP53 tumor suppressor gene, which cause it to make a defective p53 protein. The p53 protein normally causes cells with DNA damage to either pause and repair that damage or, if repair is not possible, to self-destruct. When p53 is not working, cells with DNA damage keep dividing, which can lead to further defects in other genes, and eventually cancer.

Gene changes in ARMS

Certain genes in a cell can be turned on when bits of DNA are switched from one chromosome to another. This type of change, called a translocation, can happen when a cell is dividing into 2 new cells. This seems to be the cause of most cases of alveolar rhabdomyosarcoma (ARMS). In these cancers, a small piece of chromosome 2 (or, less often, chromosome 1) often ends up on chromosome 13. This moves a gene called PAX3 (or PAX7 if it’s chromosome 1) right next to a gene called FOXO1, creating a PAX/FOX01 fusion gene. The PAX genes play an important role in cell growth while an embryo’s muscle tissue is being formed, but these genes usually shut down once they’re no longer needed. Moving one of them next to the FOXO1 gene keeps the PAX gene active, which seems to be what leads to the tumor forming.

Other translocations or other types of gene changes are also sometimes seen in ARMS. In fact, about 1 out of 4 cancers that doctors would usually classify as ARMS have been found not to have the PAX/FOXO1 fusion gene typically seen in ARMS. Doctors have found that these cancers act more like embryonal rhabdomyosarcoma (ERMS), which generally requires less intensive treatment than ARMS.

Gene changes in ERMS

Research suggests that embryonal rhabdomyosarcoma (ERMS) develops in a different way. Cells of this tumor typically have lost a small piece of chromosome 11 that came from a person's mother, and it has been replaced by a second copy of that part of the chromosome from their father. This seems to make the IGF2 gene on chromosome 11 overactive. The IGF2 gene codes for a protein that can make these tumor cells grow. Other gene changes are probably important in these tumors as well.

Other gene changes

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 haven’t been found yet.

What causes gene changes?

Researchers now understand many of the gene changes that can lead to RMS, but it’s still not clear what causes these changes. Some gene changes can be inherited from a parent. Others might just be a random event that sometimes happens inside a cell, without having an outside cause. There are no known lifestyle-related or environmental causes of RMS, so it’s important to know that there is nothing children with RMS or their parents could have done to prevent these cancers.