Maral Adel Fahmideh, PhD; Michael E. Scheurer, PhD, MPH, Baylor College of Medicine
Introduction
Primary brain tumors are the most common solid tumors in children and the leading cause of cancer mortality in this population. Pediatric brain tumors (PBTs) are heterogeneous in histopathology, molecular features, and prognosis, and they are classified into two major categories including glial and neuronal tumors (1). The most common forms of glioma in children are astrocytomas, oligodendrogliomas, ependymomas, brain stem gliomas, and optic nerve gliomas. Another rare, but often fatal glial tumor that occurs in children is diffuse intrinsic pontine glioma, or DIPG. The majority of neuronal tumors are embryonal tumors of which the most common types are: medulloblastoma, atypical teratoid/rhabdoid tumors, and central nervous system primitive neuroectodermal tumors (CNS PNETs); also known as CNS embryonal tumors, NOS (2, 3).
The frequency of different histological subtypes of PBTs varies by age. According to the Central Brain Tumor Registry of the United States (CBTRUS), in children 0-14 years old, glioma accounted for 53% of all primary brain and other central nervous system (CNS) tumors. Among gliomas, the majority were pilocytic astrocytoma (33%) followed by other low-grade gliomas (27%). Additionally, 15% of all primary CNS tumors were embryonal tumors of which medulloblastoma (62%) and atypical teratoid/rhabdoid tumors (15%) were the most common histological subtypes (4).
Incidence and prognosis of PBTs varies greatly and depends on various factors including tumor histology, tumor location, age at diagnosis, race, ethnicity, and sex. Despite their prevalence and clinical importance, knowledge on the etiology and molecular characterizations of pediatric brain tumors is limited. In this review article, we summarize the descriptive epidemiology and the current knowledge on etiology of primary pediatric brain tumors.
Descriptive Epidemiology
Incidence
The incidence of PBTs differs by age, sex, geography, race, and ethnicity. In the United States, from 2012-2016, the incidence of all primary brain and other CNS tumors in children and adolescents <20 years of age was 6.06 per 100,000 children. Approximately, 58% of cases were malignant and 42% were non-malignant (5). The incidence was reported to be higher in non-Hispanics compared to Hispanics (6.35 vs 5.14 per 100,000) as well as in Whites compared to Blacks (6.29 vs 4.71 per 100,000). Additionally, the incidence of all primary brain and other CNS tumors was higher in girls compared to boys (6.13 vs 5.98 per 100,000) (5); however, this is not consistent with previous reports (4).
According to the CBTRUS report, among children 0-4 years of age diagnosed with brain and other CNS tumors, the highest incidence was attributable to pilocytic astrocytomas (1.15 per 100,000); however, the incidence of this histological subtype decreased with advancing age. Among children aged 5-9, pilocytic astrocytoma (1.04 per 100,000) followed by malignant glioma (0.88 per 100,000) showed the highest incidence. Additionally, the highest incidence of medulloblastoma was observed among children 5-9 years of age (0.59 per 100,000). Among children aged 10-14 and 15-19, the highest incidence was attributable to tumors of the sellar region (0.86 per 100,000) and tumors of the pituitary (2.30 per 100,000), respectively (5).
Survival After Diagnosis
Survival for patients with PBTs also varies by histology, tumor location, age at diagnosis, race, and ethnicity. The 10-year survival for children aged 0-19 diagnosed with malignant brain and other CNS tumors was estimated at 72% with lowest (17%) and highest (96%) survival rates being attributable to glioblastoma and pilocytic astrocytoma, respectively. Additionally, in the United States, 96% of children 0-19 years old with non-malignant tumors survived ten years after diagnosis (5). Overall, tumors located in the brain stem showed the poorest survival compared to tumors located at any other site, while tumors of the cranial nerves showed the highest survival (4). Also, survival is better for children diagnosed at an older age, since younger children cannot be treated as intensively as older children (1, 4). Survival was reported to be poorer among non-Hispanic black and Hispanic patients compared to non-Hispanic whites (6-9).
Risk Factors
Known and Suspected Genetic Risk Factors
Cancer predisposition syndromes
There is an established increased risk of PBTs associated with rare single-gene disorders or genetic syndromes, which may occur de novo or may be inherited. However, only a small proportion (~4%) of PBTs are attributable to these rare autosomal dominant or autosomal recessive disorders. The most common genetic syndromes (and their related genes) predisposing to nervous system tumors include: Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2), Tuberous Sclerosis Complex (TSC1or TSC2), Li-Fraumeni (TP53) (10).
Family history
A modest risk of developing CNS tumors among the siblings of PBT cases has been reported. In particular, a higher risk was observed if both children have been diagnosed with medulloblastoma and PNET. Children with a parent diagnosed with a CNS tumor showed an elevated risk of developing brain tumors; however, these observed associations were based on small numbers of affected families. In general, there is limited evidence for an association between family history of cancer and non-syndromic PBTs (11, 12).
Rare variants
Due to rarity of PBTs and further rarity of familial PBTs, little knowledge is available on genetic variants contributing to the genetic architecture of familial PBTs. Backes and colleagues (13), performed a study in a family with two unaffected parents and two siblings diagnosed with glioblastoma. By using whole-exome sequencing, they identified three significant pathways containing at least three affected genes, including: focal adhesion, ECM-receptor interaction, and complement and coagulation cascades. Of all the identified genes, 32 genes were located on chromosomes 1, 11, and 22 (13).
Germline mutations associated with sporadic PBTs vary by histological subtype, and about 10% of sporadic PBT cases harbor a predisposition mutation. To date, the conducted studies have been mainly focused on high-penetrant germline mutations in known cancer predisposition genes; therefore, the contribution of rare high-penetrant mutations in the risk of PBTs is largely unknown (14). Recently, a large study, performed on childhood high-grade glioma by using whole-exome sequencing, identified that the rare germline variants associated with risk of PBTs are mainly located in 24 genes largely involved in DNA repair and cell cycle pathways (15).
Common genetic variants and sporadic brain tumors
Very few and generally small genetic association studies have been conducted on brain tumors in children and adolescents. To date, there is one published genome-wide association study (GWAS) of medulloblastoma. This study identified 13 genetic variants associated with medulloblastoma risk (16). The genetic variants associated with risk of PBTs have been mainly identified by candidate-gene association studies conducted on pooled histological subtypes of PBTs (10). The identified genetic variants mainly belong to genes involved in xenobiotic detoxification (17, 18), inflammation (18), DNA repair (16, 18-20), and cell cycle regulation (16, 19-21). It has been shown that the validated genetic variants identified by GWAS on adult glioma are also associated with risk of PBTs (22-24).
Maternal genetic effect
Despite the potentially important role of maternal genetics on the risk of PBTs by affecting the in utero environment of the developing embryo, limited knowledge is available on role of maternal genetic variations in the etiology of these tumors. Lupo and colleagues (25), in the only available study of its kind, investigated the role of maternal variation in xenobiotic detoxification genes and the risk of pediatric medulloblastoma using a case-parent triad study design. The results indicated that maternal variation in EPHX1 (rs1051740) was associated with elevated risk of pediatric medulloblastoma (RR=3.26; 95% CI 1.12-9.53) (25).
Known and Suspected Non-genetic Risk Factors
Ionizing radiation
Exposure to moderate-to-high doses of ionizing radiation is the only established environmental risk factor for PBTs (26). Compared to adults, children are more radiosensitive and have a longer life expectancy to experience the carcinogenic effects of ionizing radiation (27). There is evidence that radiotherapy for early-onset childhood cancers, particularly children who received radiation therapy for acute lymphoblastic leukemia that included exposure to the brain, is correlated with an increased risk of brain tumor development later in life (10, 26, 28). Additionally, some studies have reported that maternal diagnostic radiation during pregnancy is associated with an increased risk of brain tumors in offspring (26, 29). The effect of diagnostic radiation during early childhood on subsequent brain tumor risk was evaluated, and a 29% excess risk was reported for children exposed to one or more head CT scans (27, 29-31). This finding should be interpreted with caution since pre-existing cancer in children with high susceptibility may lead to undergoing more head CT scans (31).
Non-ionizing radiation
The effects of non-ionizing radiation, including radiofrequency, microwaves, and extremely low frequency magnetic fields (ELFs), on the risk of PBTs have been investigated by some studies. Despite the classification of radiofrequency fields as a possible carcinogen by the International Agency for Research on Cancer (IARC) in 2011, no significant associations were observed for cellular phone use or other radiofrequency radiation exposure by recent high-quality studies. In addition, in 2002, based on the available findings, IARC concluded that there are not sufficient data to classify ELFs as a risk factor for brain tumors (10, 12).
Allergic conditions
Although there is consistent evidence for an association between personal medical history of allergies and decreased risk of adult glioma, inconsistent evidence of reduced risk of PBTs associated with allergic and atopic conditions (such as asthma, wheezing, and eczema), as well as early life exposure to infections, has been reported (12, 32). It is unclear whether history of allergies and atopic diseases decrease the risk of PBTs or PBTs prevents allergic and atopic conditions (33). Therefore, Mendelian randomization studies are needed to address these questions and clarify the action of these effects, as has been conducted in adult populations (34).
Parental factors
Advanced parental age, as a marker for accumulated genetic aberrations in the parents’ DNA, has been reported to be associated with an elevated risk of brain tumors in offspring (35). There is more consistent evidence of increased risk of PBTs associated with advanced paternal age at birth than advanced maternal age at birth (12). Despite the extensive research on the association between parental occupational exposures and risk of brain tumors in offspring, inconsistent findings have been reported. However, the results from the studies of parental occupational/residential exposure to pesticides are more consistent and indicate a positive association between risk of PBTs and exposure to pesticides (10, 12, 36). Additionally, positive associations between parental high socioeconomic status as well as maternal intake of dietary n-nitroso compounds (NOCs) and risk of PBTs in offspring have been reported (10, 12).
Birth characteristics and structural birth defects
Of the investigated birth characteristics, large studies and meta-analyses provide evidence that high birth weight (>4000 g) is associated with an increased risk of pediatric CNS tumors, particularly astrocytoma and embryonal tumors (37, 38).
Approximately 7% of PBTs can be attributable to non-chromosomal structural birth defects, which is one of the most consistent risk factors for childhood cancer overall (10, 39). Large, population-based studies reported that birth defects are associated with approximately two-fold elevated risk of brain tumors in children. (10, 40, 41). Children with CNS birth defects or with a neurological anomalies showed an even higher susceptibility to developing PBTs (10, 42).
Conclusions and Future Directions
PBTs represent a complex heterogeneous group of neoplasms with different histopathology, molecular features, and etiology. Various factors including tumor histology, tumor location, age at diagnosis, sex, race, and ethnicity influence the incidence and prognosis of PBTs. Exposure to ionizing radiation and some rare genetic syndromes are the only established risk factors for PBTs; although relatively consistent evidence of positive associations for birth defects, markers of fetal growth, advanced parental age, maternal dietary NOCs, and exposure to pesticide has been reported.
Performing large, collaborative, and multi-institutional genetic studies based on SNP-array and next generation sequencing data to identify common and rare germline variants associated with risk of PBTs, in different ethnic groups, is an important research priority. Considering the heterogeneity of PBTs, the studies that aim to evaluate histology-specific risk variants are also needed. Utilizing high-quality publicly available genetic and environmental data as well as data from cancer and birth defect registries are beneficial for studies of these rare tumors. Gene–environment interaction studies will play an important role to increase our understanding of the etiology of PBTs. Incorporating genetic and environmental data may lead to the development of comprehensive risk prediction models that could be leveraged for the prevention of these tumors.
Written for the Childhood Brain Tumor Foundation
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