Do we know what causes neuroblastoma?

The causes of neuroblastoma are not completely known. But researchers have found important differences between neuroblastoma cells and the normal neuroblasts (early forms of nerve cells) from which they develop. They have also found differences between neuroblastomas that are likely to respond to treatment and those that have a poor prognosis (outlook). These differences (known as prognostic markers) are useful in choosing the best treatment for some patients (see the section, “How is neuroblastoma staged?”).

Both nerve cells and cells of the medulla (center) of the adrenal gland develop from cells in the fetus called neuroblasts. Neuroblastomas develop when normal fetal neuroblasts fail to become mature nerve cells or adrenal medulla cells. Instead, they continue to grow and divide.

Neuroblasts may not have completely matured in babies by the time they are born. In fact, studies have shown that there are small clusters of neuroblasts in the adrenal glands of some infants less than 3 months old. Most of these eventually mature into nerve cells or simply die off and do not form neuroblastomas. Sometimes, neuroblasts remaining in very young infants continue to grow and then form tumors. Some may even spread to other parts of the body. But many of these tumors will still eventually mature into nerve tissue or go away on their own.

However, as children get older, it becomes less likely that these cells will mature and more likely that they will continue to grow into a cancer. By the time neuroblastomas are large enough to be felt or cause symptoms, most can no longer mature on their own and will grow and spread unless treated.

The failure of some neuroblasts to mature and to stop growing is due to abnormal DNA inside the cells. DNA is the chemical in each of our cells that makes up our genes – the instructions for how our cells function. DNA is found in each cell's nucleus (control center), in long string-like structures called chromosomes. We usually look like our parents because they are the source of our DNA, but DNA affects more than how we look. It can also influence our risk for developing certain diseases, such as some kinds of cancer.

Some genes contain instructions for controlling when our cells grow, divide into new cells, and die. Certain genes that help cells grow and divide are called oncogenes. Others that slow down cell division or cause cells to 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.

In most cases, neuroblastoma cells have some type of chromosome changes (such as too many or too few chromosomes or missing part of a chromosome) that likely affect certain genes. Scientists are still trying to determine which genes are affected by these chromosome changes, as well as how these changes might affect the growth of neuroblastoma cells.

Some people who develop cancer have DNA mutations they inherited from a parent, which increases their risk for the disease. In rare cases, neuroblastoma seems to be due to inherited gene changes. Inherited changes in the ALK oncogene seem to account for most cases of hereditary neuroblastoma. A small number of inherited neuroblastomas are caused by changes in PHOX2B, a gene that normally helps nerve cells to mature.

Still, most neuroblastomas are not caused by inherited DNA changes. They are the result of gene changes that happen early in the child’s development, often before birth. These changes are found only in the child's cancer cells, so they will not be passed on to his or her children. Some of these genes have been found. For example, about 10% to 15% of sporadic (non-inherited) neuroblastomas have changes in the ALK gene. But the exact genes affected are not known in most cases.

Some gene changes may affect how quickly a neuroblastoma is likely to grow. For example, neuroblastoma cells sometimes contain extra copies of an oncogene called MYCN, which is often a sign that the tumor will grow quickly and may be harder to treat. On the other hand, the NTRK1 gene (which makes the TrkA protein) is often overactive in neuroblastoma cells that have a favorable prognosis. Researchers recently found that neuroblastoma cells in older children are more likely to have changes in the ATRX tumor suppressor gene. Tumors with this gene change tend to grow more slowly, but they are also harder to cure. This may help explain why younger children with neuroblastoma tend to do better long term than children who are older when diagnosed.

Researchers have found some of the gene changes that may lead to neuroblastoma, but it’s still not clear what might cause these changes. Some gene changes may be inherited. Some may have outside causes that are not yet known, but others may just be a random event that sometimes happens inside a cell, without having an external cause. There are no known lifestyle-related or environmental causes of neuroblastomas at this time, so it is important to remember that there is nothing these children or their parents could have done to prevent these cancers.