Damian Sendler: Tumors of the brain and other parts of the central nervous system (CNS) are extremely rare, but they have a significant impact on health outcomes for people of all ages. Brain and other CNS tumor epidemiology research is summarized in this article. High birth weight, non-chromosomal structural birth defects, and higher socioeconomic status were found to be risk factors for childhood and adolescent brain and other CNS tumors. When it comes to adults, increased leukocyte telomere length, a higher proportion of European ancestry, a higher socioeconomic status, and certain HLA haplotypes all increase the risk of malignant brain tumors, while immune factors reduce it.
Damian Jacob Sendler: This disease has yet to be linked to any known risk factors, but new “omics” approaches and improved detection/measurement methods will help us refine our current understanding of these risk factors and discover new risk factors for this disease.
Dr. Sendler: Although brain and other CNS tumors are extremely rare, they have a significant impact on mortality and morbidity for people of all ages. Research into the causes of brain and other CNS tumors has been ongoing for decades, but no major risk factor has been identified. The World Health Organization International Classification of Diseases on Oncology [1] lists over 100 different types of brain and other CNS tumors as histologically complex, and these tumors exhibit many of the well-known hallmarks of cancer [2, 3], such as abnormal cell growth and metabolism. Our understanding of brain and other CNS tumor causes and risk factors is being refined and expanded with the use of novel high-throughput “omics” approaches. Children/Adolescents and adults alike are at an increased risk of developing brain or other CNS tumors due to a variety of factors, including genetic predisposition.
At 0–14 years old and 15–19 years old, the most common cancer in children and adolescents is brain or other CNS tumors, followed by melanoma. Tumors of the brain and other parts of the central nervous system (CNS) are more common in children under the age of 5 than in any other age group. Non-malignant brain and other CNS tumors (age-adjusted incidence 2.60 per 100,000) are less common in this age group than malignant tumors (age-adjusted incidence 3.55 per 100,000) in children and adolescents [4••]. Tumors of the pituitary are the most common benign histology in this age group, while glioma, embryonal tumors, and germ cell cancer all occur at high rates (Fig. 1a). The incidence of these tumors in this age group has not changed significantly over the past few decades [4••, 5]. The overall survival of children and adolescents with brain and other CNS tumors varies greatly depending on the histology of the tumors, making them the leading cause of cancer-related death among those diagnosed between the ages of zero and fourteen.
A comparison of the prevalence and survival rates of primary brain and other CNS tumors in children and adults (0–19 years) and adults (20 years and older), as well as a comparison of the distribution of these tumors by behavior (CBTRUS incidence: data provided by the CDC’s National Program for Cancer Registries (NPCR) and the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program, 2013-2017; NPCR Survival Analytic file (2001–2016
The NPCR Survival Analytic File (2001–2016) is a statistical database.
Rounded percentages may not equal 100 percent. ‘All Other Malignant’ includes histologies with the ICD O 3 behavior code of /3 from choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal tumors, embryonal tumors, nerve sheath tumors, mesenchymal tumors, primary melanocytic lesions, other meningeal tumors, lymphoma, other hematopoietic tumors, Neuronal and mixed neuronal glial tumors, pineal region tumors, embryonal tumors, other tumors of the cerebral and spinal nerves, melanocytic lesions, other meningeal tumors, other hematopoetic tumors, germ cell tumors, cysts and heterotopias, and neoplasm unspecified are all included in the category “All Other Non-Malignant.”
Factors that have been studied to identify a factor that accounts for a large proportion of childhood and adolescents brain tumors have included both environmental and genetic factors. As it stands, there isn’t any evidence to support this claim. A single gene inherited disorder (less than 4% of childhood cases) and exposure to ionizing radiation are the two primary risk factors for brain and other CNS tumors in children, adolescents, and adults. A clear dose response relationship is evident in children, with carcinogenic effects of radiation being most prominent in the youngest children [8, 9]. Childhood brain and other CNS tumor genetic association studies are rare, so our understanding of genetic risk factors for these tumors in this age group is limited. In some studies, there is evidence of shared genetic risk factors between age groups for brain and other CNS tumors (as discussed in [6•]). Children with a European heritage are more likely to develop a childhood ependymoma, according to some recent studies [10, 11]. However, this association was not seen in children younger than 12 years old at the time of diagnosis [11•].
Damian Sendler
Birth weight and non-chromosomal structural birth defects are among the most recent environmental risk factors to be studied in relation to the risk of childhood and adolescent brain and other CNS tumors. According to three large meta-analyses [12–14], higher birth weight is associated with an increased risk of childhood brain and other CNS tumors. A study by Georgakis and colleagues found that children born with a birth weight of more than 4000 g had an increased risk of developing a childhood brain and other CNS tumor (Odds Ratio 1.14, 95 percent confidence interval (1.08–1.20); a higher risk for astrocytoma and embryonal tumors, but not for ependymoma [12]. Astrocytic and medulloblastoma tumors were found to be more common in children born with a birth weight greater than 4000 g, but not in children born with ependymoma [13]. Contrary to the findings of the previous studies, Bailey and colleagues found no link between birth weight and the risk of childhood cancers of the central nervous system (CNS).
Children with non-chromosomal structural birth defects are a strong and consistent risk factor for childhood cancers in general [15–17]. These findings were most pronounced in young children, aged 5 years or younger, with cancer [18, 19]. Approximately 7% of childhood brain and other CNS tumors are caused by these defects [15–17]. Studies in the past suggested that a birth defect doubled the risk of childhood brain and other CNS tumors [18–21]. The hazard ratio for developing a brain or other CNS tumor is as high as 10 for children who have a central nervous system defect or other neurological anomaly, according to a recent study that used records from 10 million live births.
An adult’s second most common cancer is a tumor in the central nervous system (CNS) [4••]. Malignant tumors of the brain and other parts of the central nervous system are rare in adults aged 20 and older (age-adjusted incidence of 22.38 per 100,000), while non-malignant tumors are more common (age-adjusted incidence 8.5 per 100,000) [4••]. Glioma is the most common malignant histology in adults, while meningioma and pituitary tumors are the most common non-malignant histologies (Fig. 1b). The incidence of glioma in this age group has not changed significantly over the past few decades [4••, 5]. Adults aged 40 and older in the United States are the sixth most likely to die from cancer caused by malignant brain and other CNS tumors. The prognosis for adults with brain and other CNS tumors differs greatly depending on the histology of the tumor (Fig. 1d).
While many potential risk factors for adult brain and other CNS tumors have been investigated, only high-dose ionizing radiation exposure has been consistently identified as a risk factor [22]. A one-Gy dose of ionizing radiation was associated with a 4.63-fold increase in the risk of meningioma, but only a 1.98-fold increase in the risk of gliomas. Glioma risk has been shown to be lower when a person has a history of respiratory allergies [23]. The vast majority of cases of brain tumors are not caused by this relatively uncommon form of radiation exposure.
It’s still unclear which environmental factors are linked to brain and other CNS tumors, but many are being studied. Because of their widespread use, cellular phones have received the most attention. As a result of the IARC’s 2011 [24] classification of radiofrequency fields (RF) as a possible carcinogen, cell phones emit these fields. There have been no significant associations between cell phone use and any type of brain or other CNS tumor since the release of the IARC report. There has been a lot of research done on extremely low frequency magnetic fields (ELFs) and brain and other CNS tumor risk. When the INTEROCC consortium looked into the link between ELF and tumors of the brain and other parts of the central nervous system, they found no evidence of a connection [25]. Another potential source of EMF exposure linked to an increased risk of brain and other central nervous system tumors is power lines. Power line electromagnetic fields (EMFs) have been linked to an increased risk of brain tumors, particularly glioma, according to a recent case–control study. More research is required to verify this link. None of the non-radiation occupational exposures have thus far shown consistent associations with risk of brain and other CNS tumors [6•].
Damian Jacob Markiewicz Sendler: Only 5% to 10% of brain and other CNS tumors are found in people with a known cancer syndrome, while the vast majority are found in people without a known cancer syndrome [27]. Brain and other CNS tumor risk is influenced by a wide range of mendelian cancer syndromes, including neurofibromatosis types I and II, tuberous sclerosis, and the Li Fraumeni syndrome (reviewed in [6•]; Table 1). Genetic polymorphisms have been studied because there are no known environmental risk factors in individuals without a family history of the disease. This is the most common malignant tumor in the brain and central nervous system (CNS), accounting for the vast majority of deaths from CNS tumors. A total of 25 single nucleotide polymorphisms (SNPs) have been linked to glioma risk in this study. These variants raise the risk of a specific type of cancer. Five of the 11 glioblastoma-specific risk SNPs and 19 non-glioblastoma-specific risk SNPs are shared by both gliomas [28••] (Table 1). Although some of the glioma-associated SNPs are part of known oncogenic pathways, it is not known what they do just yet. Telomere maintenance pathways, including risk variants near TERT and RTEL1, have been identified as the most common pathway conferring glioma risk. Many of these SNPs are associated with additional molecular subtypes ([29•]; Table 1). East Asian populations have been the focus of a number of candidate SNP studies, which have yielded both new loci associated with glioma and confirmation of loci found in European-ancestry populations (Table 1) (TERC, TERT, EGFR and PHLDB1) [30, 31]. The only GWAS of glioma in an East Asian population confirmed associations near TERT, PHLDB1 and RTEL1 and discovered two new variants. [32•]
Other types of brain and CNS tumors have also been studied genetically. The risk of meningioma was found to be influenced by two SNPs in European populations [33•] (Table 1), while the risk of primary CNS lymphomas was found to be influenced by two SNPs (Table 1). Three SNPs have been linked to an increased risk of pituitary adenoma in people of East Asian ancestry [35]. The development of a brain tumor has been linked to a variety of other genetic factors besides just the SNPs themselves. There is a link between longer leukocyte telomeres (LTL) and an increased risk of both glioma and meningioma. Glioma samples have been shown to have significantly longer telomere length than other cancers, in addition to individual level variation in LTL [38]. [6•, 39] White non-Hispanics in the United States are more likely to develop malignant brain tumors than any other ethnic group [6•, 39]. African American and Hispanic glioma cases have higher overall European ancestry than control cases, as has been found with pediatric tumors [40•].
Damian Jacob Sendler
Glioma patients have been studied epidemiologically for a number of infections. Glioma risk has been linked to members of the polyomavirus family such as BK, JC and SV40 [41, 42]. Studies on members of the herpesviridae family have yielded conflicting results. In humans, Epstein-Barr virus (herpes-simplex 1/2) in Epstein-Barr cancer has been extensively studied, but there are conflicting results when it comes to CNS tumors Although CMV has been linked to glioma, there is inconclusive evidence to support a link between CMV and glioma risk/survival and the presence of CMV in tumors [45–48]. Anti-CMV therapies valganciclovir and a pp65-based treatment have recently shown increased patient survival [49, 50]. Although CMV may not be directly involved in the development of glioma, its role in tumor growth and immune evasion has been supported by these findings and other studies. Not a virus, but a protozoan, toxoplasma gondii, has been recently linked to glioma risk (T. gondii). When two separate cohorts were compared, there was a significant association between the presence of antibodies to T. gondii and glioma risk before diagnosis (OR: 2.70; 95 percent CI: 0.96–7.62; OR: 1.32; 95 percent CI: 0.85–2.07) in both groups. There is a need for additional serologic studies on T. gondii.
the herpesvirus varicella zoster (VZV), which causes chickenpox and shingles, is the only infection that is consistently associated with an increased glioma risk [53]. Similar results have been found in serological studies of VZV antigens [54, 55]. An international meta-analysis of self-reported VZV infection from 8704 cases in the Glioma International Case Control Study found that infection with VZV reduced the risk of glioma by 20%. Glioma development may be mediated by interactions between the VZV and the host immune response, though the mechanism is still unknown. Allergic and ectopic conditions have been shown to reduce glioma risk, which is in contrast to the negative association with VZV [23]. As reviewed in [6•], allergies and other atopic conditions reduce the risk of brain tumors, particularly gliomas.
Damien Sendler: In two large international meta-analyses, allergy and ectopic conditions have been found to reduce the risk of glioma by about 20% [23, 57]. Tests on glioma patients and healthy controls have shown that higher levels of serum IgE are associated with a lower risk of developing the cancer [58, 59]. Mendelian randomization studies have been used to further investigate the genetic architecture of allergies and their relation to glioma risk [60–62]. When comparing the risk of glioma with genetically programmed allergy/atopy, these studies have found small effects of reduced risk, but the results are not conclusive and may be due to the difficulty of developing a genetic instrument for allergy and exotopia conditions.
Studies have shown that antibody responses to many viruses are heritable (32–48 percent) and that multiple host genetic loci relating to the immune response to a variety of viruses have been identified. [64–66] Genetic loci related to T-cell and signal transduction [64–66] are estimated to account for about 65% of allergic reactions. The human leucocyte antigen (HLA) has emerged as a powerful genetic regulator in both allergic reactions and the body’s response to infections. Glioma has been linked to specific HLA alleles, but studies using SNP array data are complicated by the HLA’s complexity. The UCSF Adult Glioma Study was one of the first to investigate this, with risk-increasing effects observed for B13 and B07 C07 haplotypes, and protective effects for C01 allele [67]. A32 and B55 HLA alleles were found to be associated with longer survival in GBM AGS patients in the same study. In a separate population, A32 was found to be inversely associated with GBM risk [68]. There is a 50% greater risk of glioma in heterozygous carriers of the DRB115:01–DQA101:02–DQB106:02 haplotype than in homozygous carriers (p 0.001), with significant non-additive/epistatic effects [69]. Interestingly, this haplotype has been linked to a decreased risk of developing glioma in people with a history of autoimmune disease, as well as an increased antibody response to EBV and VZV antigens [70, 71]. Glioma predisposition appears to be inversely related to the genomic architecture of T cells, NK cells, and myeloid cells, according to recent analyses of immune cell expression using LD score regression [72•]. To classify tumor-infiltrating immune cells, researchers are turning to immunohistochemistry [73] and novel methylation-based analyses [74•]. Both of these approaches aim to classify tumors based on the immune cells that have invaded the tumor. It has recently been shown that low methylation neutrophil-lymphocyte ratios (HR 2.02, 95 percent CI 1.11–3.69) are associated with significantly shorter survival times [75]. Glioma risk is complicated, and more research into the interactions between genetic loci, blood cell proportions, and their relationship to allergies and infections is needed.
SEP (socioeconomic status) has been linked to an increased risk of adult CNS tumors, according to a growing body of evidence from various studies [76–79, 80••]. The first quartile of county income has a 10 percent, 11 percent, and 14 percent higher risk of glioma than the second, third, and fourth quartiles, according to SEER data [77]. Non-Hispanic whites were found to have a higher risk associated with higher SEP in a recent SEER analysis [80••]. Two registry-based studies of childhood CNS malignancies in California and Denmark have shown that this relationship appears to not only exist in adult CNS tumors but also in childhood CNS tumors [81•, 82•]. Tumors in patients with lower SEP may go unreported due to a diagnostic bias, but the accuracy of surveillance and the magnitude of the effect suggest that this bias alone does not account for the association. The ‘hygiene hypothesis’ [83], which proposes that immune exposures to allergy and infection may be altered by SEP, is another possibility for the association between higher SEP and an unidentified risk factor.
Despite the fact that no single risk factor for brain and other CNS tumors has been identified, there are a variety of approaches that can be taken to improve our knowledge of these conditions. Comprehensive research into this disease will necessitate the application of “omics” approaches with high throughput, enhanced detection and measurement of environmental exposures, expansion to more diverse populations, synergy between germline and somatic variants, and inclusion of all types of clinical data (such as imaging). New directions will help us refine our current understanding of these factors and discover new risk factors for the disease.
