Rhabdomyosarcoma is a type of cancer that develops from skeletal muscle cells that have failed to fully mature. It is a malignant tumor, meaning it grows uncontrollably and can spread to other parts of the body. Understanding what causes rhabdomyosarcoma involves looking at the complex changes in the cells’ genetic material and the environment that leads to this abnormal growth.
At its core, rhabdomyosarcoma arises when the normal process of muscle cell development goes wrong. Normally, muscle cells start as immature cells called mesenchymal cells, which then develop into mature skeletal muscle cells. In rhabdomyosarcoma, these immature cells begin to multiply uncontrollably without maturing properly, forming a tumor. This failure in normal development is often triggered by genetic mutations or alterations in the DNA of these cells.
One of the main causes of rhabdomyosarcoma is genetic mutations that affect how cells grow and divide. These mutations can be inherited or can occur spontaneously. In many cases, specific genetic changes are found in the tumor cells. For example, some rhabdomyosarcomas have fusion genes, which are abnormal genes created when parts of two different genes join together. These fusion genes produce proteins that drive the cancer cells to grow and survive. A well-known example is the fusion of the PAX3 or PAX7 gene with the FOXO1 gene, which is common in the alveolar subtype of rhabdomyosarcoma. These fusion proteins act like switches stuck in the “on” position, pushing cells to divide endlessly.
Besides fusion genes, other genetic alterations include amplifications or mutations in genes that control the cell cycle, such as CDK4. When these genes are altered, they can cause the cells to bypass the normal checks and balances that prevent uncontrolled growth. This leads to the formation of tumors. Some rhabdomyosarcomas also show changes in tumor suppressor genes, which normally act as brakes on cell division. When these brakes fail, cancer can develop.
Environmental factors and exposures have not been clearly linked to causing rhabdomyosarcoma, but some rare inherited conditions increase the risk. These include Li-Fraumeni syndrome, neurofibromatosis type 1, and Beckwith-Wiedemann syndrome. These syndromes involve inherited mutations in genes that normally protect against cancer, making affected individuals more susceptible to developing rhabdomyosarcoma and other cancers.
Rhabdomyosarcoma can develop in muscles that are not typically cancer-prone in adults, such as those around the eyes or in the bladder wall. This suggests that the cells of origin might be early muscle precursor cells or mesenchymal stem cells that have the potential to become muscle but have not yet committed to a specific muscle type. The exact cell of origin is still a subject of research, but it is clear that the tumor arises from cells that are supposed to become skeletal muscle but get stuck in an immature, proliferative state.
The two main subtypes of rhabdomyosarcoma, embryonal and alveolar, have different genetic causes and behaviors. Embryonal rhabdomyosarcoma, more common in younger children, often shows loss of heterozygosity at certain chromosome regions and other genetic changes that disrupt normal muscle development. Alveolar rhabdomyosarcoma, more common in older children and teenagers, is strongly associated with the fusion genes mentioned earlier, which lead to a more aggressive disease.
In summary, rhabdomyosarcoma is caused by genetic mutations and alterations that disrupt the normal development and growth control of muscle precursor cells. These changes lead to uncontrolled cell division and tumor formation. While inherited genetic syndromes can increase risk, most cases arise from spontaneous mutations in the cells destined to become skeletal muscle. The complexity of these genetic changes and their effect
