The etiology of pediatric brain tumors remains largely unknown.
Less than 5% can be attributed to a genetic predisposition, and even fewer are linked to ionizing radiation or other environmental factors. For most patients, no predisposing factors are as yet apparent.
The following table summarizes many of the etiologic factors. To learn more about each click on the individual factors for a more thorough explanation.
Summary of etiological factors associated with pediatric brain tumors:
| Etiological Factor | Effect of Exposure on Risk |
Associated risk with brain tumor |
Increase |
Several genetic syndromes are associated with the development of pediatric neoplasms:
|
|
Increase |
High dose exposure is the most established environmental risk for pediatric brain tumors |
|
Inconclusive (suggested increase) |
Maternal ingestion of N-nitroso compounds or their precursors may increase risk of pediatric brain tumors |
|
Inconclusive (suggested decrease) |
Maternal ingestion of Folate, Vitamin C, and Vitamin E are all associated with a decreased risk of pediatric brain tumor |
|
Inconclusive (suggested increase) |
Preconceptional paternal smoking may be linked to development of pediatric brain tumours |
|
Inconclusive (suggested increase) |
This is not proven. |
|
Inconclusive (suggested increase) |
Maternal exposure to bacterial, viral or parasitic infection has sometimes been observed |
|
Inconclusive (suggested increase) |
Penthrane has been associated with brain neoplasms |
|
Immune Disorders |
Increased risk of CNS lymphoma |
Acquired immunodeficiency post transplant Ataxia-telangectasia Wiskott- Aldrich syndrome |
Inherited (Genetic) Syndromes
Ionizing Radiation
- High-dose exposure to ionizing radiation is the most established environmental risk factor for pediatric brain tumors to date.
- Most radiation-induced brain tumors are caused by cranial radiation (XRT) for the treatment of other cancers.
- Children who have RT for acute lymphoblastic leukemia (ALL) have a seven-fold increased risk of developing any type of second cancer, and a twenty-two fold increase in CNS neoplasms.
- Most second cancers are seen in patients that received their original diagnosis of ALL at an age of less than five years.
- Most resulting tumors are high-grade astrocytomas or meningiomas.
The offspring of mothers who have undergone diagnostic prenatal radiation also have an increased incidence of childhood CNS tumors. In recent years, however, this exposure has become less of a concern as the use of X-ray pelvimetry prior to delivery is outdated. Also, for many procedures the radiation doses are lower than in the early part of the twentieth century.
N-nitroso compounds
- N-nitroso compounds are formed by the nitrosation process that occurs under acidic conditions, such as in the stomach.
- Two main classifications of N-nitroso compounds are N-nitrosamines and N-nitrosamides.
- N-nitrosureas, a form of N-nitrosamides, are particularly carcinogenic in animals, and are strongly linked to the development of CNS brain tumors.
- The role of nitrites and cured meats in the development of human brain cancers remains controversial since people are exposed to continuous low levels of N-nitroso compounds throughout their lives.
Dietary sources of N-nitroso compounds are foods that have been exposed to nitrogen oxides or that contain nitrite. This includes nitrite-cured and smoked meat, fish, cheese, and beer. Some epidemiological studies indicate that the maternal consumption of smoked meats is the dietary factor most consistently associated with childhood brain tumors. However, the nitrosation process can be inhibited by vitamins C and E. In these studies, daily prenatal vitamin intake or high fruit and vegetable intake by the mother are both associated with a decreased risk of childhood brain tumors in the offspring. The precursors are also prevalent in antihistamine and anti-diuretic medications.
Vitamins
- Maternal consumption of multivitamins throughout pregnancy may decrease the incidence of pediatric brain tumors.
- Vitamin C and vitamin E inhibit the nitrosation process in the stomach, preventing the contribution of N-nitroso compounds to the development of brain tumors.
- This is supported by the finding that the risk associated with the maternal consumption of cured meats is decreased when the mother takes multivitamins.
Folic acid is of particular interest in the prevention of brain cancers.
- Folate plays a protective role from the development of neural tube defects.
- A common mechanism for the development of neural tube defects and PNETs has been suggested, suggesting that folate may also play a role preventing the latter.
- A significant decrease in risk of PNET development has been found with the maternal consumption of folate supplements.
- The folate receptor is overexpressed in the molecular analysis of CNS malignancies, particularly ependymomas. However, the cellular role of folate in childhood brain tumors is yet to be elucidated.
Tobacco
- Exposure to tobacco smoke during gestation, as a contributing factor to the development of pediatric brain tumors, is umproven.
- Some of the chemical components of tobacco are known carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and nitrosamines.
- Epidemiological studies fail to demonstrate that maternal smoking during and before pregnancy is association with childhood brain cancer in offspring.
Preconception paternal smoking
- Linked to offspring brain cancers in epidemiological studies.
- Association was found to be significant for brain tumors in children under 5 years of age.
- Preconception paternal exposure may increase the risk of cancer in offspring because paternal germ cells are continually undergoing spermatogenesis and the replication of genetic material, making these cells more susceptible to mutagenic changes.
- The sperm of smokers has been found to have a 1.7-fold increase in DNA-adducts over sperm of those who have never smoked, as well as a 107% increase in reactive oxidative species.
- Cancer in the offspring of male smokers may be due to DNA damage or adduct formation in the sperm.
Molecular Genetic Changes
- Inactivation of the tumor suppressor protein p53 is believed to contribute to brain carcinogenesis in human astrocytomas and glioblastomas.
- One-third of malignant pediatric gliomas have been found to have p53 mutations, with these mutations being less common in patients under 3 year of age.
- The p53 mutation, as well as increased expression of the p53 protein, are associated with shorter survival.
- p53 mutations are very rare in PNET.
Low-frequency electromagnetic Fields (EMF)
- An increased public and scientific interest in the contribution of low-frequency EMF exposure to the development of brain tumors has yielded only inconclusive results.
Infectious Agents
- No consistent correlation between an infection and pediatric brain tumors.
- One case-control study found that children of mothers who had a documented viral infection during pregnancy exhibit an11-fold increase in risk of developing a malignant nervous system tumor.
- Examples of such maternal viruses include rubella, mumps, varicella, and herpes zoster.
Exposure to polyoma viruses has also been linked to the development of brain cancers. Simian Virus 40 (SV40) has been increasingly linked to primary brain cancers in infants and children, and has been shown to induce brain cancers in experimental animals. The JC virus, another polyoma virus, has been detected in both malignant and non-malignant tumors in every cell type in the CNS. The JC virus protein, T-antigen, is believed to interfere with the cell cycle, namely the inactivation of p53. This evidence suggests that infection with a polyoma virus may be an inciting event in the development of pediatric brain tumors.
Maternal Medications
The antibiotic Metronidazole, or “Flagyl”, is commonly prescribed during pregnancy to treat bacterial vaginosus and trichomoniasis, both of which are linked to preterm labor. Metronidazole is believed to contain active nitro-reduced metabolites that cause structural DNA damage, cell functional impairment, and microbe death. It readily crosses the placenta and accesses fetal circulation. However, while it has been linked to the development of neuroblastomas, it has not been linked to CNS tumors.
An increased risk for all tumor types has been found when mothers are given penthrane (an anaesthetic) during delivery. Other anaesthetics have not been associated with childhood brain tumors.
