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Cancer. Author manuscript; available in PMC Apr 29, 2010.
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PMCID: PMC2861559
NIHMSID: NIHMS186048

Brain Tumor Epidemiology: Consensus from the Brain Tumor Epidemiology Consortium (BTEC)

Melissa L. Bondy, Ph.D., Michael E. Scheurer, Ph.D., Beatrice Malmer, M.D., Ph.D., Jill S. Barnholtz-Sloan, Ph.D., Faith G. Davis, Ph.D., Dora Il’yasova, Ph.D., Carol Kruchko, Bridget J. McCarthy, Ph.D., Preetha Rajaraman, Ph.D., Judith A. Schwartzbaum, Ph.D., Siegal Sadetzki, M.D., M.P.H., Brigitte Schlehofer, Ph.D., Tarik Tihan, M.D., Joseph L. Wiemels, Ph.D., Margaret Wrensch, Ph.D., and Patricia A. Buffler, Ph.D., on behalf of the Brain Tumor Epidemiology Consortium

Abstract

Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings possibly due to small sample sizes in individual studies and differences between studies in subjects, tumor types, and methods of classification. Individual studies have generally lacked sufficient sample size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups such as pediatric brain tumors, the etiology of rare glioma subtypes, such as oligodendroglioma, and meningioma, which not uncommon, has only recently been systematically registered in the US. There is also a pressing need to bring more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. We review the group’s consensus on the current state of scientific findings and present a consensus on research priorities to identify the important areas the science should move to address.

Keywords: Glioma, Meningioma, Epidemiology, Genetics

Introduction

Epidemiologic studies of glioma have examined many risk factors over the past several decades; however, there are few consistent findings. The inconclusive results could possibly be due to small sample sizes in individual studies and differences between studies in subjects, tumor types, and methods of classification. Individual studies have generally lacked sufficient sample size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. Since brain tumors have been an orphan disease because of the small numbers, the funding to study these tumors has been relatively limited. The Brain Tumor Epidemiology Consortium (BTEC) convened a group meeting to develop a consensus on research priorities to identify the important areas the science should move to address. The following discussion is the current state of literature and presents the group’s consensus on important research needs to drive the science forward over the next decade. Although the epidemiologic literature on brain tumors is, in many areas, inconclusive, there are many promising areas to pursue in future research. Here we include an overview of the descriptive epidemiology, and risk factors such as inherited susceptibility, ionizing radiation, non-ionizing radiation, immune function (including allergies and infections), established neurocarcinogens, and metals.

Methodology of Review and Assessment of Important Research Areas

In preparation for the BTEC group meeting, two experts who had previously published in a specific area were assigned to write an overview of their area of expertise before the meeting in Berkeley. Generally, larger studies with conclusive results published in the last 25 years were considered for reference by search of PubMed. The review was not intended as an exhaustive overview of the literature covering all studies reporting inconclusive results; a review of this magnitude has been previously published.1 All background chapters were presented at the meeting and small discussion groups were formed from the attending delegates. Each research area of interest was discussed in the small groups, and each group prioritized which research topics were considered most important for future studies. Finally, a large room discussion with all 45 delegates was performed based on the initial recommendations from the small groups. The full discussion of each topic was followed by a vote from the entire group identifying the priority research areas of major interest to the majority of the group,

Incidence and Mortality

The annual global age-standardized incidence of primary malignant brain tumors is ~3.7 per 100,000 for males and 2.6 per 100,000 for females2, 3. Rates appear to be higher more developed countries (males, 5.8 and females, 4.1 per 100,000) than in less developed countries (males 3.0 and females 2.1 per 100,000). Approximately 20,500 individuals (11,170 males and 9,330 females) were diagnosed with primary malignant brain tumors in 2007 in the US (www.cancer.org). The incidence of both primary malignant and non-malignant brain tumors in the US is ~14.8/100,000/year,4 with white males having the highest rate. Males also generally have higher rates of primary malignant brain tumors while females have higher rates of non-malignant tumors, primarily meningiomas. Distributions of tumor types vary substantially by age group and interested readers are referred to the Central Brain Tumor Registry of the United States (CBTRUS; www.cbtrus.org) for a complete compilation of brain tumor statistics. Data from several national cancer registries support differences in the epidemiology of brain tumors in children versus adults. For example, in Sweden, medulloblastoma (23.5%) and low grade glioma (31.7%) are the most common type of tumors in pediatric cases aged 15 years and younger; this is very different compared to the adult cases, in whom high-grade glioma (30.5%) and meningioma (29.4%) are the most common types of adult primary brain tumors (data taken from the Swedish Cancer Registry). Data from CBTRUS support these differences in the United States as well.

Worldwide age-standardized mortality for primary malignant brain tumors is ~2.8 for males and 2.0 for females per 100,000.2 As with incidence, estimated mortality is higher in more developed countries (4.1 and 2.7/100,000 for males and females, respectively) than in less developed countries (2.2 and 1.6 per 100,000 for males and females, respectively). U.S. mortality rates for primary malignant brain tumors are 5.6 and 3.7 per 100,000 for males and females, respectively. In the US, 5- and 10-year survival rates are ~29.1% and 25.3% (ACS; www.cancer.org), respectively, and differ significantly by histology and age. For example, glioblastoma multiforme (GBM) has a 5-year survival rate of 3.3%, while lower grade gliomas, such as pilocytic astrocytoma, oligodendroglioma, and ependymoma have 5-year survival rates of over 70%, while astrocytoma (not otherwise specified), anaplastic astrocytoma, malignant glioma, and lymphoma have 5-year survival rates less than 40%. Overall, and for most histologies, five-year survival rates decrease with age (www.cbtrus.org). However, there are some histologic types for which survival is poorer among children and the elderly (e.g. GBM and ependymoma). Conflicting reports, some with methodologic problems, find variation in survival by race/ethnicity.59 Caucasians had a 5-year relative survival of 33.5%, while African-Americans had a 5-year relative survival rate of 37.0%. Similar analyses using SEER data showed African-Americans had similar or poorer survival than Caucasians 7 but results were incompletely adjusted for important prognostic factors (e.g., age at diagnosis, treatment patterns and tumor histologies). After adjustment, African-Americans showed a 13% higher risk of death for primary malignant brain tumors and 40% higher risk of death from low-grade tumors compared to White non-Hispanics.6

In summary, progress in diagnostic technologies and ascertainment, particularly for non-malignant brain tumors, may account for much of the modest increase in incidence. Changes in tumor classification and coding are likely responsible for some of the increases in incidence for brain tumors histologies such as oligodendroglioma, astrocytoma, and not otherwise specified. Further diagnostic advances will produce rising incidence in specific diagnoses. The influence of gender on brain tumor incidence rates is quite consistent over time and geographic area, with a preponderance of glioma among males and meningioma among females.

Risk Factors

Table 1 summarizes the associations found for a variety of factors with adult glioma and meningioma. There is consensus among brain tumor epidemiologists that variations in study designs, population characteristics, information sources, measurement, and classification have limited the ability to make conclusive associations of specific types of adult brain tumors with individual risk factors. In addition, studies have varied in their reliance on proxy and historical information and standards of precision and completeness for data sources used. With respect to environmental exposures, future studies should pay greater attention to whether or not suspect agents can cross the blood brain barrier (BBB) or whether they can reach the brain via other routes.

Table 1
Non-occupational Risk Factors for Adult Brain Tumors

Genetic Susceptibility: Genetic Syndromes

Studies of syndromes, familial aggregation, linkage, and mutagen sensitivity in adults suggest genetic susceptibility to gliomas. Although the genetic syndromes caused by rare inherited mutations and associated with higher risk of BT 10 account for few cases, they provide an important starting point for identifying candidate genes and pathways for gliomagenesis. Syndromes including gliomas or medulloblastoma, with gene names and chromosome location, are neurofibromatosis 1 and 2 (NF1, 17q11; NF2 22q12), tuberous sclerosis (TSC1 9q34, TSC2 16p13), retinoblastoma (RB1; 13q14), Li-Fraumeni (TP53 17p13) and Turcot’s syndrome and multiple harmatoma (APC 5q21, hMLH1 3p21.3, hMSH2 2p22-21, PMS2 7p22, PTEN 10q23.3). The roles of more common variants in many of these genes (and related pathways) in sporadic gliomas are as yet unknown.

Genetic causes of brain tumors apart from well-known syndromes have yet to be clarified; however, brain tumors aggregate in families.11 In addition, a segregation study suggests multifactorial inheritance, and linkage studies point to the 15q23 region.12, 13 Large collections of glioma families for more extensive linkage analyses are being collected in the international Gliogene study of familial glioma (www.gliogene.org).

Genetic Susceptibility: Specific Genetic Polymorphisms

Researchers have studied a number of polymorphisms in relation to glioma, most commonly in DNA repair, carcinogen metabolism, and immune function genes either because of their plausible relationship to carcinogenesis or from consistently observed associations between allergies and glioma (see below). Although some promising results have been found as noted below, too few studies have been conducted of any polymorphisms to assure consistency. Inherited variation in DNA repair represents a major category of genes extensively studied with respect to cancer because of their importance in maintaining genomic integrity. Glioma and/or glioma subtypes have been significantly associated with variants in ERCC1, ERCC2, the nearby gene GLTSCR1 (glioma tumor suppressor candidate of unknown function), PRKDC (aka XRCC7), MGMT, and most recently, CHAF1A. 1419 ATM haplotypes have been associated with meningioma and cell cycle genes more weakly with glioblastoma.20, 21 Recently, a polymorphism in BRIP-1 was associated with meningioma, which might provide functional link to the previous described association to breast cancer.22 Intragenic SNPs in the Ki-ras and ERCC2 genes were associated with a 1.7-fold increase in meningioma risk, and a significant interaction was found between radiation and cyclin D1 and p16 SNPs.23 Simultaneous consideration of DNA repair with other relevant (e.g., inflammation or cell cycle control) pathways would allow proper evaluation of larger sets of polymorphisms. For example, most gliomas exhibit dysregulation of p53 whether through mutation or some other mechanism, and MDM2 is a key guard in this pathway. The few established exogenous environmental causes of glioma are therapeutic or high-dose radiation and possibly high-dose chemotherapy for cancers at sites other than the brain.2427 Genetic factors determine the degree of risk from these exposures. Children treated with cranial irradiation and intensive antimetabolite therapy for acute lymphocytic leukemia and those with germline polymorphisms leading to low or absent thiopurine methyltransferase activity are significantly more likely than those without such polymorphisms to develop BT. Metabolizing enzymes such as glutathione transferases have been investigated in several studies with inconsistent results.28, 29

Abundant evidence suggests inherited susceptibility acts in glioma risk, but describing its forms is challenging. The two main, possibly complementary, research efforts are familial linkage studies currently undertaken in the Gliogene study, and disease association studies. Although large-scale genome wide association studies of glioma have much to commend them, for brain tumors there are serious limitations of relatively small sample sizes and heterogeneity within and between types of gliomas and other primary brain tumors. These increase the chances of both false positive and false negative results. Consequently, it will be important to continue to prioritize polymorphisms based on biologic knowledge to develop strong prior hypotheses for testing subsets of pathways, genes and polymorphisms. Several groups now plan large-scale association studies, including the UCSF Adult Glioma study, a European-M.D. Anderson Cancer Center Consortium, and a Mayo study of oligodendroglioma. UCSF is also developing a web site to catalog and prioritize genes and polymorphisms of interest with glioma etiology and prognosis (www.snplogic.org).

Tumor studies have provided valuable information both for categorizing tumors and suggesting chromosomal regions important in glioma pathogenesis. Cytogenetic and array-based comparative genomic hybridization studies of gliomas identify copy number changes (deletions, amplifications, gains) in several regions. Deletions and loss of heterozygosity suggest tumor suppressor genes, while amplifications and gains may point to genes involved in tumor initiation or progression. The more regularly observed of these, which may vary by histologic type include gains and deletions in 1p, deletion of 4q, amplifications and gains of 7, deletions of 9, 10 and 11, and loss of 13, 19 and 22. Coincidentally, several well-known tumor suppressor genes and oncogenes occur in these regions. These also indicate substantial genetic and gene expression heterogeneity within and between tumor grades and between histological types.30 However, the degree to which the mature tumor is independent of the “causal” environmental or genetic pathways is unknown, as is whether variability of dysregulated pathways among tumors reflects different causes. In addition to these histological differences, GBM can be separated further into “secondary” GBM thought to have progressed from lower grade tumors and “primary” or “de novo” GBM with no clinically apparent precursor. Interestingly, TP53 mutation and EGFR amplification correlate with the type of GBM.30 Tumors with TP53 mutations more often are secondary GBM, while de novo GBM more likely harbors EGFR amplification. Despite some inconsistencies between studies, case-control findings support smaller case series hypothesizing that astrocytic tumors arise via different pathways and reflect different causal mechanisms. Therefore, molecular subtyping is likely to be useful in the future as an adjunct to histology for tumor classification.

Ionizing Radiation Exposure

Certain forms and doses of ionizing radiation are generally accepted causes of brain tumors.31, 32 A-bomb studies, 32, 33 nuclear test fall-out data, 34, 35 therapeutic radiation for cancer and benign conditions,3642 and occupational and environmental studies 4347 connect ionizing radiation to tumorigenesis. 1, 24, 33, 4851 The first conclusive evidence of an association of ionizing radiation and brain tumors comes from a follow-up study of Israeli children undergoing radiation therapy for tinea capitis with a mean dose to the brain of 1.0–6.0Gy. 51, 52 The cohort includes 10,834 irradiated individuals with both matched population and sibling control groups.50 With follow-up, meningioma strikingly increased (RR=9.5; 95% CI: 3.5–25.7), and glioma marginally so (RR=2.6; 95% CI: 0.8–8.6).51 A later follow-up of the cohort showed the ERR/Gy for the irradiated group was 4.63 (95% CI: 2.43 – 9.12) and 1.98 (95% CI: 0.73 – 4.69) for benign meningiomas and malignant BT, respectively,53 with an inverse trend with age at irradiation noted among the malignant BTs only. For both tumors, risk was elevated after a latency of ≥30 years, dose responsive but unassociated with gender or origin.

The high meningioma incidence of A-bomb survivors was shown for residents of Nagasaki 54, 55 and Hiroshima.56 The difference between the Japanese and the Israeli studies may arise from A-bomb survivors’ lower radiation exposure compared to the tinea capitis cohort,54 and A-bomb radiation mainly affecting adults, tinea capitis radiation primarily children. A 6.5-fold increase in risk of meningioma among exposed versus unexposed populations of Hiroshima survivors was also reported. 57 The latest study reported a statistically significant dose-response for all nervous system tumors combined, indicating exposure to even moderate doses (<1Sv) of radiation is associated with elevated incidence of CNS tumors. 33

A follow-up study of childhood nasopharyngeal radium exposure (545 subjects and 1158 controls) found a RR = 30.9 of BTs for the children exposed. 58 The Childhood Cancer Survivor Study (CCSS) among 5-year survivors of childhood cancer (n=14,361) identified subsequent primary CNS tumors among 116 members, most often meningioma (n=66) and glioma (n=40), occurring a median of 17 and 9 years, respectively, from original diagnosis. 40 Exposure to radiation therapy as treatment for the primary cancer was associated with ORs of 6.78 (95% CI, 1.5–30), 9.94 (95% CI, 2.2–45.6) and 7.07 (95% CI, 2.8–18.1) for glioma, meningioma, and all CNS tumors combined, respectively. A limitation of the CCSS and some survival studies is that survival of children with cancer treated with radiation during the first 5 years following diagnosis and treatment is not included, and some treatment-related BTs may arise during this first five years post diagnosis.

Cohort studies of nuclear industry workers, 43 radiologists and X-ray technologists 47, 59 report effects of ionizing radiation occupational exposure with leukemia, but not BT, risk. A study of US radiology technologists from 1983–1998, found 53 cases of BT, yielding a SIR of 0.95. 46 A case-control study 60 of newly diagnosed CNS tumors, aged 25–74, reported a RR of 2.1 (95% CI: 1.0–4.3) for meningioma development in subjects receiving dental radiography at least annually, compared with less than every 5th year. However, most studies of diagnostic ionizing radiation and BT risk show no association. 6164 Alternatively, a high rate of meningioma was found in families in which additional siblings were irradiated;65 thus, lending support for the role of genetic susceptibility for these tumors.

Non-Ionizing Radiation: Electromagnetic Fields and Radio Frequency Cell Phones

The association of exposure to non-ionizing radiation, specifically exposures in the radio frequency range (RF) or electromagnetic fields in the extremely low frequency range (EMF ELF) and development of primary BTs remains unresolved. Of particular interest is the questionable relationship between both gliomas and meningiomas and cellular phone use.66 These exposures are ubiquitous, and recent research focuses principally on mobile phones because these RF exposures occur near the head and brain. The possible influence of currently acceptable low-level RF exposures on carcinogenesis has been suggested by some studies and warrants further investigation.67 While the relative rarity of primary BTs necessitates a case-control study design, these studies experience severe limitations with exposure assessment due to reliance of personal recall of cases and controls of their RF exposures (i.e., cell phone use). The INTERPHONE study, coordinated by IARC, included investigations from thirteen EU countries using a common protocol for inclusion of cases and controls and for data collection using the same questionnaire. 68, 69 Between 2000 and 2003, the study recruited 2,708 cases of gliomas, 2,409 cases with meningiomas and 1,000 cases of acoustic neuroma and their respective population-based controls. Several country-specific results from these studies have been published.7074 These results, which overall do not identify increased risks for malignant or non-malignant tumors in most studies, suggest, in some studies, a non-significant increase in risk associated with longer duration of use or longer follow-up time. Publication of the combined results on cell phone use related to the risk for these tumors, i.e. the INTERPHONE study, will be forthcoming. In the same vein of the INTERPHONE Study, a study is being established to examine the synergistic effect between chemicals and metals and EMF.

Allergies, Atopic Diseases and Systemic Infections

Meta-analyses of an extensive literature based on numerous case-control and two cohort studies indicates that there is an inverse association of self-reported allergies with glioma that is unlikely to be due to chance or methodologic biases alone.75 Furthermore, one study indicated that glioma cases had lower post-diagnostic serum IgE levels (which are associated with atopic allergies) than controls.75 However, since recall bias could affect the self-reporting of allergies, or the presence of the tumor itself could affect post-diagnostic IgE levels, investigators have also examined whether inherited polymorphisms in genes positively associated with allergy (interleukin (IL)13, IL4, and IL4 receptor-alpha) might be inversely associated with glioma.7679 Such results (if found) would argue against recall bias and reverse causality as the explanations for the associations of allergies, IgE levels and glioma. While definitive results from such studies are elusive, some consistent associations were reported for an IL13 polymorphism and an IL4R haplotype, both linked with allergy, with survival and/or case-control status.79, 80 It remains unclear whether allergies protect against tumors or whether immunosuppressive gliomas inhibit allergies, as two additional studies on IgE and glioma are not consistent with the aforementioned studies. First, the presence of atopic disorders at time of diagnosis, not prior history, was associated with reduced glioma risk in one additional study.76 Second, it was shown that a cohort of patients initially tested for total serum IgE levels and subsequently linked to a population-based cancer registry showed no association of IgE levels with subsequent cancer (however glioma was not addressed specifically).78 The original manuscript on IgE and glioma also reported that non-IgE related allergies were inversely related with glioma,75 suggesting that IgE per se may not be on the causal pathway driving the association, but rather another related immune factor.

If the inverse association between allergies, IgE, relevant polymorphisms and glioma is real and not due to bias or possible reverse causality, what mechanisms could explain the association? Known tumor immunology is thought to be based on cell-mediated immune mechanisms that are controlled by Th1-CD4+ cells.81 These cells enhance cytotoxic T-cell and natural killer cell activation via IFN-γ, and suppress Th2-CD4+ T cells which are critical for enhancing allergic phenotypes and depend on IL-4 and IL-13. However, gliomas are known for expressing high amounts of cytokines that inhibit both Th1 and Th2 immunity and are secreted by T-regulatory (Treg) CD4+ cells. Glioma patients that do exhibit Th2-type phenotypes are protected against glioma as mentioned above, which may result from the attraction of eosinophils to the tumor site.81, 82 Another possibility is that immunosuppressive regulatory T cells (Tregs) may be the vehicle for inhibition of anti-tumor immunity, and allergy is a clinical manifestation that is correlated both with hyperallergic (Th2) and enhanced cellular (Th1) immunity, both which may help inhibit tumors.8386 Evidence of the Treg inverse association with IgE is strengthened by the observation that a mutation in FOXP3, central to Treg function, leads to high serum levels of IgE and intense allergic inflammation.83 Moreover, atopic conditions are characterized by relatively low levels of Tregs and allergic desensitization (treatment-induced immunosuppression of allergic conditions) is mediated by Tregs.84 One possible mechanism for protection against glioma conferred by allergies is that, people with allergies have lower levels of Tregs and therefore may be better able to mount an anti-tumor response than people without allergies.85 A corollary to this exists with regard to tissue transplantation, whereby infiltration by Treg cells is necessary for successful grafts of foreign tissue.87 Similarly a tumor is a foreign tissue which would engraft more successfully with inhibition of immune rejection afforded by more Tregs. Higher Treg levels produced in response to symptoms associated with elevated IgE levels (e.g. asthma exacerbations) have an anti-inflammatory effect that inhibits early glioma development by blocking T-cell activation and angiogenesis,88 mechanisms that may be enhanced by the the use of non-steroidal anti-inflammatory drugs (NSAIDS) which have also been linked to a lower risk of glioma.86, 87,88 In addition, Tregs help determine whether infections will be chronic or acute by accumulating at sites of chronic infection, hampering immunity and allowing pathogens to persist. Acute infections are related to decreased cancer risk at several sites, including gliomas;89 while chronic infections are associated with an increased cancer risk.87 A history of infections and colds is also associated with reduced glioma risk (OR=0.3, 95% CI = 0.1, 0.8).87 People reporting at least one febrile episode in the ten years before diagnosis of glioblastoma have a lower risk than people reporting none.79 Also, the observed inverse association between anti-varicella zoster virus IgG levels and glioma (described below) might be accounted for by an inadequately modulated Treg response resulting in the extinguishing of viral latency in patients that then have a higher future risk of glioma. Individuals (among the controls without tumors) which have an productive Treg response are likely to strike a balance between VZV maintenance and suppression, and similarly react in a productive manner against a nascent brain tumor. However, any findings related to the immune system and glioma based on case-control studies may reflect preclinical immunosuppressive effects of the glioma.

Viruses

Polyomaviruses, including JC, BK and simian (SV40) virus, have been found in human glioma tissue and have induced brain tumors in animals.89 A nested case-control study observed no statistically significant associations between viral IgG for these viruses and glioma but was based on a small sample.91 A study of contaminated polio vaccine found lower risk of gliomas in birth cohort members exposed to contaminated vaccine in childhood or infancy than unexposed members;92 however, this cohort effect may be due in part to improved brain tumor diagnostic technology.

Since some herpes viruses can establish latency in the nervous system, they also have been plausible candidates for research. One report showed that glioma tissue from 27 tumors expressed multiple human cytomegalovirus (HCMV) -gene products in contrast to control and normal tissues.94 Three additional studies failed to replicate these findings;9597 however, two newer reports support the original findings related to HCMV.98, 99 Inflammatory stimuli can activate HCMV gene transcription, and can induce malignant transformation and transactivate other oncogenic viruses associated with malignant gliomas, such as JCV.100 Two independent case-control series found inverse correlations between serum IgG antibodies to varicella zoster virus (VZV) and glioma.90, 93 Consistent with these inverse associations are those between self-reported history of chicken pox in the same subjects and there was a dose-response inverse relationship of higher IgG levels with lower glioma risk.93 In contrast, no evidence exists for an association between glioma and antibodies to herpes simplex, Epstein-Barr virus or CMV.

Neurocarcinogens (NOCs) and Metals

Previous studies of associations of primary brain tumors with chemical and physical agents has been reviewed extensively.2427 Despite decades of research, the only environmental agent that is conclusively associated with brain tumor risk is ionizing radiation.

Risks from specific neurocarcinogens have yet to be identified; however, the continued occurrence of brain tumor clusters leaves open the question of the effect and extent of their exposures. Early studies focused on nitroso compounds and polycyclic aromatic hydrocarbons because of their abilities to induce brain tumors in animal models, but studies have yet to conclusively link brain tumors to exposures to these or other neurocarcinogenic compounds (aliphatic and alicyclic hydrocarbons, methylene chloride, mercury, glycerol polyglycidyl, polychlorinated biphenyls, and epichlorohydrine exposures) possibly because of small numbers, tumor heterogeneity, unknown latency period or period of vulnerability of the brain to these compounds, recall difficulties, and other methodologic issues.9095 Observations of an association of drinking water and brain tumors suggest that ingestion of an environmental contaminant has an impact,61, 96, 97 perhaps from chlorinated sources 98 such as chloroethane, a byproduct of treatment of sewage and wastewater, or nitrate/nitrite contamination99 leeching into drinking water supplies. In addition, one occupational study reported elevated risk of glioma, especially low-grade gliomas, associated with exposure to "metals".100

Cadmium is a type I carcinogen associated with human lung, renal, bladder, breast, liver, and stomach cancers and ranks first among suspect metals for brain tumors.101107 It is commonly used in the production of common consumer goods, and can be found in the environment.108111 The major sources of personal exposure are occupation, smoking, and diet.101, 112,113 Studies support the carcinogenic effects of cadmium,106, 114 and show its effects on increasing the permeability of the BBB;115 however, only one epidemiologic study (an occupational cohort study of 413,877 Finnish women) found weak evidence for an association between cadmium and brain tumors, but neglected to control for cadmium in tobacco smoke and diet.116

Lead also occurs widely in the environment and is classified as a probable human carcinogen, although evidence is weak for CNS tumors.117 Most studies of lead-exposed human populations report chromosomal toxicity and interference with repair of DNA damage 118, 119 leading to increased in vitro mutagenicity.120 Despite limitations with exposure assessment, the direction of risk in most cohort studies of lead exposure has been positive.121 In addition, most,122124 but not all 125, 126 case-control studies of occupational exposures to lead report slight increased risk of brain tumors in the highest levels of lead exposure.123 Studies of lead and meningioma risk consistently report a statistically significant, positive association,124, 125, 127, 128 and one study found suggestive evidence of effect modification by a common polymorphism in the delta-aminolevulinic acid dehydratase (ALAD) gene.125

Prognostic factors

Glioma survival and prognostic information comes primarily from clinical trials and population registry data. Clinical trial groups provide useful, oftentimes more complete information on prognostic factors from cases whose pathology has been centrally reviewed. However, it is still unfortunate that the majority of adult patients do not have access to or are not enrolled in clinical trials, limiting the representativeness of the sample. Alternatively, survival estimates based on population registry data have the advantage of representing the full spectrum of glioma patients but the disadvantage that pathologic diagnoses vary considerably depending on the neuropathologist, the time and site of diagnosis, and the diagnostic criteria used.129131

Investigators currently try to identify and understand tumor markers or patient characteristics influencing survival or response to treatment.17, 132145 Histologic type and grade, age, extent of resection, tumor location, radiation therapy and some chemotherapy protocols have been consistently and convincingly linked to survival in both clinical trial and population registry data. 146154 Karnofsky Performance Status (KPS) at diagnosis and other measures of mental and physical functionality also predict survival for GBM and anaplastic astrocytoma patients.147, 151153

One difficulty in identifying prognostic factors in rapidly fatal glioblastoma is the limited survival time of nearly all patients. Until the advent of treatment with temozolomide, median survival from time of diagnosis for patients with glioblastoma was 6–7 months and had not improved in over 20 years. Temozolomide treatment has improved average survival to 12–14 months. There is a very strong and consistent inverse relationship of age and survival for the various histologic subtypes of glioma (www.cbtrus.org) and younger patients benefiting more from radiation therapy than older patients.155 Additionally, combined loss of chromosome 1p and 19q in oligodendrogliomas is a consistent favorable prognostic indicator,133, 156164 while, in astrocytic tumors, amplification/overexpression of EGFR is common in older patients, especially with anaplastic astrocytomas.18, 165, 166 EGFR amplification may also be associated with poorer survival in younger (55–60 years) adults with GBM.143, 167 A recent large prospective trial of newly diagnosed GBM suggested that methylation of the MGMT promoter in GBM tumor samples marked improved outcome,168 especially among patients who received front-line temozolomide.16

Recent studies assessing glioma prognosis from expression profiles showed a relationship of survival with abnormal expression of neurogenesis genes, cell proliferation and mitosis genes, and extracellular matrix genes.134, 138 Additionally, gene expression changes across the genome accompanied loss of chromosome 10 and copy number loss of 10 and gains of 7, 19 and 20.138 Small sample sizes, typical of expression array studies, make these findings preliminary; however, genome-wide screens invite possible validation in larger studies.

A few studies have provided potentially fruitful areas of discovery of genetic variation related to glioma survival, e.g. signaling pathways for growth factors, cell cycle regulators, modifiers of drug metabolism and radiation and immune response. Common gene polymorphisms influence response to cancer therapies, prognosis and survival,169, 170 including EGF, GSTP1 and GSTM1, HLA A*32 and B*55, and GLTSCR1 S397S and ERCC2 D711D.19, 132, 139, 144

Neurocognitive impairment is commonly associated with primary brain tumors with 91% of patients experiencing at least one area of deficit compared to the normal population, and 71% demonstrating at least three deficits. 171 Even subtle cognitive deficits can significantly limit a patient’s daily life, and unrecognized, may impact a patient’s ability to adhere to a therapeutic regimen without significant assistance. Standardized neurobehavioral measures may be used as an index for determining treatment outcomes for brain tumor patients.172 In fact, improvement in neurocognitive functioning or delay in neurocognitive impairment are acceptable end points for clinical trials, and neurocognitive functioning has been demonstrated to predict tumor progression and predict survival with CNS tumors.173176 However, studies observe wide variation in incidence of cognitive dysfunction,177182 perhaps from underlying differences in host genetic susceptibility. For example, subjects with no known neurologic disease perform more poorly on tests of memory and executive function if they carry an “at risk” allele in the APOE, COMT, and BDNF genes.183185 These may mediate cognitive reserve putting individuals with the variant alleles at greater risk for treatment-related symptoms affecting neurocognitive functioning and quality of life, but none of these genetic factors have been explored in brain tumor patients.

Conclusions

Although the epidemiologic literature on brain tumors is, in many areas, inconclusive (Table 1), there are many promising areas to pursue in future research (Table 2). One primary area of prioritization is to develop and identify additional funding sources for the epidemiological investigation of brain tumors; this is particularly important for childhood brain tumors. Due to the rarity of these tumors, it is difficult for any single institution to gather the appropriate number of cases; therefore, collaborative grants are necessary and more difficult to fund due to the large budget associated with these multi-institution studies. Researchers are eager to leverage funds from many sources, including federal granting agencies and private foundations, to bring about such studies. The GLIOGENE study is the first of such efforts to come out of BTEC.186 A second priority for the group was to enhance collaborative science with data that already exist by pooling datasets from completed studies that examined similar research questions. This is another way to overcome the power issues from individual studies. However, pooling data is an arduous task that itself takes time, effort, and money to complete. One way BTEC identified to overcome these hurdles is to identify junior investigators within the group to partner with senior investigators and lead a pooled analyses of an interesting topic. To help in this endeavor, several investigators volunteered to initiate a questionnaire designed to aid in the pooling of datasets, and potentially of biospecimens, for such projects. A third priority area identified at the meeting was the inclusion of a research agenda related to non-malignant brain tumors (e.g. meningioma) which make up a good proportion of all brain tumors. To date very few epidemiological studies have been completed on this tumor; the majority coming from the Tenea capitis cohorts in Israel. However, another collaborative grant originating from BTEC investigators has been funded to focus on meningiomas. Again the main obstacle to overcome was obtaining a sufficient number of cases to perform a meaningful analysis. A fourth area of interest was the development of a better understanding of the biology related to exposure in the brain. This topic, in particular, cuts across most of the individual research topics and relates more to the honing of our tools of exposure assessment. One essential challenge in this effort is the lack of extensive information on how exposures interact with and by-pass the blood-brain barrier. Related to this is the challenge of obtaining good measures of exposure for certain agents; for example, if systemic measures of exposure have the same meaning in the brain or how to measure chemical exposures with relatively short half-lives but long-term effects on the brain. The group has identified experts in blood-brain barrier biology and in environmental exposure assessment to contribute knowledge and practical experience to BTEC. These continued collaborations will be key in moving the science forward and identifying biomarkers of exposure to physical and chemical agents to complement more traditional self-reported exposures, insofar as possible.

Table 2
Areas for Further Investigation in Brain Tumor Epidemiology Research Areas and Priorities

In addition to prioritizing specific research topics, the future research agenda for brain tumors requires more comprehensive communication and collaboration among the scientific community than has been achieved. This reality is valid for all brain tumors, but particularly for childhood brain tumors where the numbers to conduct a sufficiently large study is greatly limited in single geographic areas, especially considering the myriad types of childhood brain tumors. Large, collaborative efforts will be needed to study the many factors that may have etiological importance for childhood brain tumors such as viruses, inherited susceptibility, immune response or host immunological status. The role of genetic, developmental, and environmental factors in both adult and childhood brain tumors will be better understood with large-scale genetic and epigenetic analyses, along with rapidly evolving bioinformatics and data analytic methods, and with improved exposure assessments. Given the relative rarity of any individual type of brain tumor, increased collaboration and communication among interested researchers with mechanisms to bring in junior investigators are among the highest priorities.

The fundamental challenges inherent in the study of brain tumors are no longer insurmountable in the age of high-speed electronic communications, genomics and bioinformatics. We believe it is time to consider comprehensive collaborations at the national and international levels that would not have been possible for earlier generations. Not unlike the efforts to accumulate worldwide human experience in combating climate change, there is a real opportunity to gather comprehensive information. Such collaborative studies are essential to enable us to compare information gathered in the same fashion from subjects across the nation and the globe.

Acknowledgments

Sources of Support: National Brain Tumor Foundation, Gold Sponsor, Sustaining Partner; Pediatric Brain Tumor Foundation, Silver Sponsor; The Preuss Foundation, Bronze Sponsor

Footnotes

List of BTEC Members (alphabetical order)

Phyllis Adatto, Jill Barnholtz-Sloan, Fabienne Bauchet, Luc Bauchet, Melissa Bondy, Jennifer Brusstar, Patricia Buffler, Mary Ann Butler, Elizabeth Cardis, Tania Carreon-Valencia, Jeffrey Chang, Anand Chokkalingam, Charles Cobbs, Jimmy Efrid, Paul Graham Fisher, Jim Gurney, Trisha Hartge, Dora Il-yasova, Alice Kang, Carol Kruchko, Amy Kyle, Rose Lai, Sharon Lamb, Ching Lau, Beatrice Malmer, Bridget McCarthy, Roberta McKean-Cowdin, Eckart Meese, Catherine Metayer, Dominique Michaud, Isis Mikhail, Lloyd Morgan, Beth Mueller, Michael Murphy, John Neuberger, Manuela Orjuela, Harriet Patterson, Susan Preston-Martin, Preetha Rajaraman, Steve Rappaport, Avima Ruder, Siegal Sadetzki, Michael Scheurer, Brigitte Schlehofer, Joerg Schlehofer, Judith Schwartzbaum, Jenni Spezeski, Patricia Thompson, Tarik Tihan, Rob Tufel, Kevin Urayama, Joseph Wiemels, John Wiencke, Margaret Wrensch

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