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While there are a few known risk factors for neuroblastoma, the cause of most neuroblastomas is not known. Still, researchers have found important differences between neuroblastoma cells and the normal neuroblasts (early forms of nerve cells) from which they develop.

How normal cells become neuroblastoma cells

Nerve cells and cells in the medulla (center) of the adrenal gland start out as neuroblasts in a growing fetus. Most often, neuroblasts grow and develop into mature cells. Neuroblastomas can occur when normal fetal neuroblasts do not become mature cells, but instead continue to grow and divide.

Some neuroblasts might not have matured completely by the time a baby is born. Most of these eventually mature into normal nerve cells over time, or they simply die off and do not form neuroblastomas.

But sometimes, neuroblasts remaining in very young infants continue to grow and form a tumor. Many of these tumors will still eventually mature into nerve tissue or go away on their own. But as children get older, it becomes less likely that these cells will mature, and more likely that they will grow into a cancer.

Why some neuroblasts don't mature

The reason some neuroblasts don't mature is because they have changes in the DNA inside the cells. DNA is the chemical in each of our cells that makes up our genes, which control how our cells function. The DNA in our cells is in long, string-like structures called chromosomes.

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

• Certain genes that help cells grow, divide, or stay alive can sometimes change to become oncogenes.
• Genes that help keep cell division under control, repair damaged DNA, or cause cells to die at the right time are called tumor suppressor genes.

Cancers can be caused by DNA changes that create oncogenes, or that turn off tumor suppressor genes. These gene changes can sometimes be inherited from a parent (which is rare with neuroblastomas), or they may happen during a person's lifetime as cells in the body divide to make new cells.

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

Acquired versus inherited gene changes in neuroblastoma

Most neuroblastomas are the result of gene changes in neuroblasts that happen during the child’s development, sometimes even before birth. What causes these acquired gene changes is not known. They might be just be random events that sometimes happen inside cells, without having an outside cause.

These acquired gene changes are found only in the child’s cancer cells, so they will not be passed on to their children.

In rare cases, neuroblastoma occurs as a result of gene changes inherited from a parent. Inherited changes in certain genes account for most hereditary (familial) neuroblastomas:

• Changes in the ALK oncogene account for most cases of inherited neuroblastoma.
• Changes in PHOX2B, a gene that normally helps nerve cells mature, account for a small number of inherited neuroblastomas.

Some neuroblastoma gene changes can affect a child’s outlook

Some other gene changes seem to affect how quickly a neuroblastoma can grow:

• Neuroblastoma cells sometimes have extra copies (amplification) of the MYCN oncogene, which is often a sign that the tumor will grow quickly and might be harder to treat.
• If the NTRK1 gene (which makes the TrkA protein) is overactive in neuroblastoma cells, the neuroblastoma might have a better outlook.
• 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 they are diagnosed.

It's still not clear what causes many of the gene and chromosome changes that can lead to neuroblastoma. There are no known lifestyle-related or environmental causes of neuroblastomas, so it's important to remember that there is nothing these children or their parents could have done to prevent these cancers.