An Introduction to Neuroblastoma
Neuroblastoma is a solid tumor cancer that arises from immature nerve cells, called neuroblasts, which are most often found in an embryo or fetus. It is one of the most common cancers diagnosed in infants and young children, with the majority of cases appearing before the age of five. These neuroblasts are part of the sympathetic nervous system, which controls the body’s automatic "fight or flight" responses. In a healthy child, these cells mature into functioning nerve cells, but in neuroblastoma, they grow uncontrollably and form a tumor.
Tumors can form anywhere along the sympathetic nervous system, but they most commonly start in the adrenal glands located on top of the kidneys. The behavior of these tumors varies dramatically. Some are low-risk and may even disappear on their own through a rare process called spontaneous regression, particularly in infants. Others are high-risk, growing aggressively and spreading quickly to other parts of the body like bone marrow, liver, and skin.
This wide spectrum of behavior is largely determined by the tumor's specific genetic makeup. Scientists have identified several key genetic factors that drive the disease, which can be broadly divided into inherited risks that run in families and spontaneous changes that occur by chance in the tumor cells themselves.
Familial Neuroblastoma: Inherited Genetic Risk
While most neuroblastoma cases are sporadic, a small fraction (1-2%) is hereditary. In this form, known as familial neuroblastoma, a specific gene mutation that increases cancer risk is passed down from a parent to a child.
The ALK Gene
The most common gene implicated in familial neuroblastoma is ALK (Anaplastic Lymphoma Kinase). The ALK gene provides instructions for a protein that is crucial for the development of nerve cells. When certain mutations are inherited in this gene, the resulting ALK protein can become locked in an "on" position, constantly signaling for immature nerve cells to grow and divide, which can lead to a tumor.
The PHOX2B Gene
Another gene linked to inherited neuroblastoma is PHOX2B. This gene acts as a master regulator, controlling other genes involved in forming the sympathetic nervous system. An inherited mutation in PHOX2B disrupts this process, preventing nerve cells from maturing properly and predisposing them to cancer. These mutations are also associated with other rare disorders of the nervous system, such as congenital central hypoventilation syndrome (CCHS).
Inheritance and Risk
These gene mutations are typically passed down in a dominant pattern, meaning a child only needs to inherit one faulty copy from a parent to have a higher risk. However, inheriting the gene is not a guarantee of developing cancer. Many people can carry the mutation without ever getting sick, a phenomenon scientists are still working to understand. This suggests that other genetic or environmental factors may be required to trigger the disease.
Somatic Mutations: Drivers of Sporadic Neuroblastoma
The vast majority of neuroblastomas are sporadic, caused by genetic changes that occur by chance within tumor cells during a child's development. These alterations, called somatic mutations, are not inherited and are confined to the cancer itself.
MYCN Amplification: The Gas Pedal
The most significant somatic alteration in this cancer is MYCN amplification. The MYCN gene normally helps control cell division. In aggressive neuroblastomas, cells mistakenly create hundreds or even thousands of extra copies of this gene. This amplification leads to a massive overproduction of the MYCN protein, which acts like a gas pedal stuck to the floor, driving relentless tumor growth and marking the disease as high-risk.
Somatic ALK Mutations: A Target for Therapy
The ALK gene, which is a primary cause of familial neuroblastoma, can also be mutated sporadically within the tumor itself. As with the inherited form, these somatic mutations lock the ALK protein in an "on" state, driving cell growth. This discovery has been critical for treatment, as it makes the ALK protein a key target for precision drugs called ALK inhibitors, which can block this faulty signal.
ATRX Mutations: Enabling Immortality
The ATRX gene helps protect the ends of our chromosomes, known as telomeres. When mutations disable ATRX, this protection is lost, leading to severe instability in the cell's genetic code. This allows cancer cells to bypass the normal limits on cell division, making them effectively immortal. ATRX mutations are often associated with more aggressive disease, particularly in older children and adolescents.
Chromosomal Alterations and Their Prognostic Significance
Beyond mutations in single genes, the overall structure of a tumor's chromosomes provides crucial clues about its behavior. Many neuroblastomas feature large-scale rearrangements where entire chromosomes or large sections are gained or lost. These patterns are powerful predictors of a patient's prognosis.
Whole Chromosome Changes and Better Outcomes
In some low-risk tumors, cancer cells contain extra copies of entire chromosomes. This condition, called hyperdiploidy, is surprisingly linked to a more stable tumor and a better prognosis for the patient. Identifying this pattern often guides doctors toward less intensive treatment strategies.
Segmental Changes and High-Risk Disease
In contrast, the gain or loss of large chromosome segments is a hallmark of high-risk neuroblastoma. These segmental aberrations signal a high degree of genomic instability, where the cell's DNA is disorganized and prone to further errors. This genetic chaos fuels aggressive tumors that grow rapidly and are more likely to resist treatment.
Key Prognostic Markers
Certain segmental changes are particularly strong indicators of a poor outcome. The most notable are the loss of the short arm of chromosome 1 (1p deletion) and the gain of the long arm of chromosome 17 (17q gain). These two alterations are often found together in aggressive, MYCN-amplified tumors, as they remove protective genes while adding genes that promote cancer growth.
Common Genetic Variants and Susceptibility
In addition to rare, powerful mutations that directly drive cancer, scientists have found that common genetic variations can also influence a child's susceptibility to neuroblastoma. These variants are not defects but are widespread in the general population, and each contributes a small amount to overall risk.
Variants Near the CASC15 and MYCN Genes
A region on chromosome 6 near the CASC15 gene contains common variants linked to high-risk neuroblastoma. This area is located close to the MYCN gene, and while the variants don't alter MYCN directly, they are thought to influence its regulation, making it easier for the gene to become amplified in developing nerve cells.
BARD1 Gene Variants
Common variants within the BARD1 gene on chromosome 2 are also associated with an increased risk of developing high-risk, MYCN-amplified neuroblastoma. The BARD1 protein normally acts as a tumor suppressor. It is believed these variants may create a slightly less effective version of the protein, weakening its ability to protect cells from becoming cancerous.
The LMO1 Gene Variant
Researchers have identified a common variant in the LMO1 gene on chromosome 11 that directly contributes to tumor formation. LMO1 is an oncogene, meaning its overactivity can promote cancer. This specific variant creates a binding site for a protein that boosts the LMO1 gene's activity in neuroblasts, increasing the risk of developing neuroblastoma, though typically the non-aggressive forms of the disease.
