Incidence

The traditional source of descriptive data on brain tumors has been the Surveillance, Epidemiology, and End Results (SEER) program sponsored by the National Cancer Institute (NCI). This program collects population-based cancer data on approximately 26% of the U.S. population (including cancer registries for nine states) to gauge national trends in cancer incidence and survival (National Cancer Institute, 2010). Until recently these data encompassed only malignant tumors; however, effective January 2004, all cancer surveillance registries are required to expand their primary brain tumor data collection to include tumors of benign or uncertain behavior (Benign Brain Tumor Cancer Registries Amendment Act; Public Law 107-260). The Central Brain Tumor Registry of the United States (CBTRUS) established in 1992 is the nation’s largest population-based registry of primary brain and central nervous system tumors, compiling information from 47 population-based cancer registries (CBTRUS, 2010).

Incidence estimates differ according to the inclusion or exclusion of nonmalignant brain tumors. The American Cancer Society estimated the diagnosis of approximately 22,020 new cases of malignant primary CNS tumors in the United States in 2010 (American Cancer Society, 2010). For 2010, CBTRUS estimates approximately 23,720 new cases of malignant and 39,210 nonmalignant primary CNS tumors in the United States (CBTRUS, 2010). The annual incidence rate for malignant brain cancer for all races from 2004 to 2006 was 7.2 per 100,000 person-years and 11.5 per 100,000 person-years for primary nonmalignant brain tumors (CBTRUS, 2010).

Mortality and Prognostic Factors

Although primary malignant brain tumors account for only 2% of all cancers and are one-fifth as common as breast or lung cancer, they contribute to substantial morbidity, and prognosis is poor. The 5-year survival rate for primary malignant brain tumors (36% between 1999 and 2005) is the sixth lowest among all types of cancer (following pancreas, liver, esophagus, lung, stomach, respectively) despite having increased over the past 30 years (from 24%) (American Cancer Society, 2010). The 5-year survival rates vary substantially by histological subtypes, 79.1% for oligodendroglioma, 27.4% for anaplastic astrocytoma, and 4.5% for glioblastoma (CBTRUS, 2010). Malignant CNS tumors accounted for approximately 13,140 deaths in 2010 (CBTRUS, 2010). Age-specific mortality rates from brain tumors among all races demonstrate gradual increases with each decade until age 55, after which the rate increases dramatically (Fig. 52A.1).

Fig. 52A.1 United States mortality rates for malignant brain and other nervous system cancer for 2002-2006, by race.

Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality—All COD, Public-Use With State, Total U.S. for Expanded Races/Hispanics (1990-2006), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2009. Underlying mortality data provided by NCHS (www.cdc.gov/nchs).

Young age and lower pathological grade are favorable prognostic factors for primary brain tumors (CBTRUS, 2010). Less significant predictors of favorable prognosis include long duration of symptoms, absence of mental changes at the time of diagnosis, cerebellar location of the tumor, small preoperative tumor size, and completeness of surgical resection.

Gender and Race

A slight male predominance exists in the incidence of malignant CNS tumors (7.5 per 100,000 person-years for men versus 5.2 per 100,000 person-years for women) (SEERS, 2010). However, when assessing nonmalignant and malignant CNS tumor types together, the incidence rate in men is lower than in women (14.4 per 100,000 person-years for men versus 16.9 per 100,000 person-years for women; SEERS, 2010). A partial explanation of this gender disparity is the predominance of meningiomas in women (8.2 per 100,000 person-years) compared to men (3.7 per 100,000 person-years) (CBTRUS, 2010). Fig. 52A.2 compares the incidence rates of malignant brain tumors among whites and blacks. Compared to blacks, whites have a higher incidence of malignant brain tumors for both sexes; white males have an incidence rate of 8.4 per 100,000 person-years compared to black males at 3.7 per 100,000 person-years, whereas white females have an annual incidence rate of 6.5 per 100,000 person-years versus an annual incidence rate of 3.3 per 100,000 person-years among black females (Ries et al., 2006). Mortality rates among whites is higher (5.0 per 100,000 persons; 2002-2006) than among blacks (2.0 per 100,000 persons; 2002-2006) (SEERS, 2009), and 5-year relative survival rates are lower among whites (35%) than blacks (41%) (American Cancer Society, 2010). Comparisons between other racial groups within the United States are difficult because of the small numbers of cases, but incidence rates of malignant brain tumors among Asian Americans and Native Americans are lower than for either white or black Americans.

Fig. 52A.2 United States incidence rates for malignant brain cancer for 2000-2007, by race and sex.

Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence—SEER 9 Regs Public-Use, Nov 2009 Sub (1973-2007), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2010, based on the November 2009 submission.

Temporal Trends

Several studies have documented rising incidence rates for brain tumors in a number of industrialized countries. These increases appear confined mainly to the elderly population, with no clear ethnic, gender, or geographical differences. Overall, incidence rates among whites in the United States increased by 1.5% annually between 1975 and 1988 and leveled off between 1988 and 2001 (SEERS, 2010).

The increases in incidence observed in the United States are in accordance with observations in other parts of the world. The responsible factors remain unclear, but at least part of the increase is the result of more complete case ascertainment because of improved diagnostic technology and better access to health care and clinical specialization. The increase in brain tumor incidence correlates with the introduction of noninvasive diagnostic technology including computed tomography (CT) in the 1970s and magnetic resonance imaging (MRI) in the 1980s. In a study using CBTRUS data, the authors reported increases in the incidence of most glioma subgroups but decreases in the incidence of “not otherwise specified” (NOS) subgroups, suggesting that changes in classification and coding of brain tumors are likely to be responsible for some of the observed time trends (Jukich et al., 2001). However, the same study identified increases in the incidence of ependymomas and nerve sheath tumors, which were less likely to be artifacts of improvements in diagnosis.

Geographical Trends and Migrant Studies

Many other countries also experienced increased brain tumor incidence rates over the past 30 years. The highest rates are in industrialized nations such as the United States, Canada, Australia, and the United Kingdom; developing nations have lower incidence rates (Parkin et al., 2005). Generally, brain cancer incidence appears associated with level of economic development; concomitant differences in the availability of diagnostic technology (CT, MRI, neurosurgical technology) and access to health care may account for some of the observed disparities. However, even within the United States, a significant variation in the incidence of primary brain tumors exists among the states. Hawaii has the lowest rate (3.9 per 100,000 person-years), and Maine has the highest rate (8.0 per 100,000 person-years) (State Cancer Profile, 2010) (Fig. 52A.3). In contrast to international trends, a clear relationship between these rates and economic conditions does not exist.

Fig. 52A.3 Incidence rates for brain and other nervous system cancer in United States by state. Incidence rates (cases per 100,000 population per year) are age-adjusted to the 2000 US standard population (19 age groups: <1, 1-4, 5-9, …, 80-84, 85+). Rates are for invasive cancer only (except for bladder which is invasive and in situ) or unless otherwise specified. Rates calculated using SEER* Stat. Population counts for denominators are based on Census populations as modified by NCI. The US populations included with the data release have been adjusted for the population shifts due to hurricanes Katrina and Rita for 62 counties and parishes in Alabama, Mississippi, Louisiana, and Texas. The 1969-2008 US Population Data File is used with SEER November 2010 data. The 1969-2008 US Population Data File is used with NPCR January 2011 data.

(Created by statecancerprofiles.cancer.gov)

In a study of Italians who migrated to Argentina, brain tumor mortality rates were lower among the migrants than in the host country (Roman, 1998). This suggests environmental factors may influence the development of brain tumors. However, disparities in completeness of case ascertainment in the countries under study complicate the interpretation of this study.

Primary Central Nervous System Lymphoma

The epidemiology of primary central nervous system lymphoma (PCNSL), a type of non-Hodgkin lymphoma, deserves special comment. A dramatic increase in the incidence of PCNSL occurred over the past few decades. This parallels a doubling of the incidence rate of systemic non-Hodgkin lymphoma over the past 4 decades. The incidence peaked in the early 1990s and has since decreased. The primary factor behind the rising incidence is the acquired immune deficiency syndrome (AIDS) epidemic. From 2% to 6% of individuals with AIDS develop PCNSL at some point in their disease course (Fine and Loeffler, 1999). The incidence of AIDS has decreased along with the rate of PCNSL since the beginning of the 1990s. However, AIDS does not fully account for the total increase in the incidence of PCNSL (Rubenstein et al., 2008). Recent studies suggest a continuing increased PCNSL incidence among non-AIDS populations (Haldorsen et al., 2007; Makino et al., 2006).

Study Designs

Analytical epidemiology involves identifying risk factors for particular diseases using the application of case-control or cohort study designs. The case-control study design has been the most commonly used in the search for brain tumor risk factors. In a case-control study, the basis for subject classification is the presence (case) or absence (control) of the outcome of interest (e.g., brain tumor). An exposure of interest (e.g., head trauma) is then determined in a uniform manner for cases and controls. An odds ratio (OR) of disease for the exposed compared to the unexposed is generated. Case-control studies are most useful in the study of uncommon diseases (e.g., brain tumors) or those with a long period between the exposure of interest and the development of disease. In a cohort study, subject selection is from the population, and the presence or absence of a particular exposure is determined during recruitment when the subjects are free of disease. Participants are followed forward in time to ascertain the development of the outcome/disease of interest. Cohort studies are most useful when the outcome under study is common. Recent large cohort studies with long follow-up periods identified sufficient cases to examine lifestyle exposure in relation to brain tumor incidence.

Methodological Challenges

In addition to the usual problem of selection bias with the case-control study design, recall bias may be an especially important limitation in retrospective case-control studies of brain tumors. Individuals with brain tumors often have cognitive and language difficulties. Therefore, reliable exposure assessments are difficult to achieve. To address this issue and to include patients who died of brain cancer before study recruitment, some case-control studies have used proxies (e.g., next of kin) to obtain information on the patient; unfortunately, this method is not accurate because proxies often misreport the patient’s exposure. Another shortcoming of observational studies is the tendency to group all brain tumors together as one entity. Given brain tumor heterogeneity, this grouping may hide underlying associations unique to one subtype of tumor. Although exceptions exist, small effects and marked inconsistencies across studies characterize most exposures analyzed. This chapter provides a review of the major categories of exposure.

Radiation

Occupational Studies

Several occupational studies focusing on brain tumors in cohorts of workers who share common potentially harmful exposures report standardized incidence or mortality ratios using expected rates from the general population. Detection bias may occur because working adults with health insurance may be more likely to undergo diagnostic tests. This may lead to better ascertainment of brain tumors in the worker cohort as compared to the general population and potentially result in spurious associations. In general, data on occupational exposures and brain tumors are inconsistent. Small numbers of cases, imprecise methods of exposure assessment, potential confounding, and bias have complicated interpretation of many studies. Study validity is often questionable, and better exposure assessment using biological measures of exposure is mostly lacking.

Several observational studies have found that workers in “white collar” professions have higher rates of brain tumors (Brownson et al., 1990; Carozza et al., 2000). Some of these occupations, such as laboratory research and health professions, involve radiation or chemical exposures, which suggests a possible biological plausibility for a causal relationship. Alternatively, detection bias may account for the excess risk in professionals, because they are more likely to have health insurance and seek medical attention. However, higher rates of brain tumors among professionals in Sweden, where health care is free and available to all citizens, suggests that detection bias may not fully account for the observations (McLaughlin et al., 1987).

Farming as an occupation and residence on a farm have been associated with an elevated risk of brain tumors in several epidemiological studies (meta-analysis RR 1.30; 95% CI, 1.09-1.56) (Khuder et al., 1998). Agricultural workers have exposures to several chemicals in the form of pesticides, herbicides, and fungicides. Similar to other occupational studies, one limitation of studies on agricultural workers is the use of job classification as a proxy for nonspecific chemical exposures. Studies with more detail on individual exposure to pesticides and herbicides have not reported convincing associations with brain tumors (Ruder et al., 2009; Samanic et al., 2008). Reports of increased risks for brain tumors also exist for workers in the vinyl chloride, petrochemical, and rubber industries. Other studies have found an increased risk among aircraft pilots, firefighters, welders, glass manufacturers, tile makers, and metal cutters. However, these findings have been inconsistent over time (Samkange-Zeeb et al., 2010).

Despite the large number of studies in several occupational settings, an increased risk of brain tumor development based on occupational status is not established. The reported studies are characterized by significant design flaws and yielded conflicting results.

Head Trauma

Head trauma is a potential risk factor for brain tumor development. The evidence is strongest for meningiomas and less convincing for gliomas (Wrensch et al., 2000). Anecdotal reports of brain tumors arising after head trauma date back to Harvey Cushing in 1922. Cushing reported the presence of a head scar or skull depression in 8% of meningioma patients. Experimental studies have also implicated physical trauma as a co-carcinogen. An excess risk of meningiomas in persons with a history of serious or repetitive head trauma has been observed in several case-control studies (Preston-Martin et al., 1989, 1998). Other studies have not confirmed an increased risk among children with head injuries (Gousias et al., 2009; Gurney et al., 1996).

Ionizing radiation may be a confounding factor in studies of head trauma and brain tumors. Individuals with a history of head trauma are more likely to have had skull x-rays. Recall bias is another factor complicating interpretation of case-control studies of head trauma and risk of brain tumors. Persons with brain tumors may be more likely to recall minor and major episodes of head injury compared to controls. One study reporting a positive association between head trauma and risk of brain tumors found no association when the definition of head trauma was restricted to episodes requiring medical attention. In a cohort study with an average of 8 years of follow-up, individuals hospitalized for head injury were not at higher risk for subsequent nonmalignant and malignant brain tumors after removing the first year of follow-up; detection bias was likely responsible for the higher risks observed in the first year (Inskip et al., 1998). No association was established between head trauma and brain tumor in a similar cohort with an average follow-up of 10 years (Nygren et al., 2001).

Acoustic neuroma (nerve sheath tumor of cranial nerve VIII) was associated with acoustic noise (trauma) of 10 years’ duration in a case-control study (OR 2.2; 95% CI, 1.12-4.67) (Preston-Martin et al., 1989). A blinded review of job histories was the basis for noise exposure. In a study with a larger sample, a similarly elevated risk of acoustic neuroma was observed among individuals reporting loud noise exposure from any source (OR 1.55; 95% CI, 1.04-2.30) (Edwards et al., 2006). The association was stronger among individuals with exposure to loud noise from machines, power tools, or construction equipment (OR 1.79; 95% CI, 1.11-2.89) or to loud music (OR 2.25; 95% CI, 1.20-4.23) (Edwards et al., 2006). Experimental studies of tissue destruction and repair following acoustic trauma support the biological plausibility of this association.

N-Nitroso Compounds

N-nitroso compounds (NOC) are potent carcinogens in animal models. N-nitroso compounds include nitrosamines, which require metabolic activation to a carcinogenic form, and nitrosamides, which do not require activation. It is well established that nitrosamines can form endogenously from foods treated with sodium nitrite and that certain foods such as bacon and beer contain preformed nitrosamines (Lijinsky, 1999). Although preformed nitrosamine levels in beer and nitrite levels have declined substantially since the 1980s, the small amounts of nitrosamines in food are nonetheless significant because of the possibility that humans are more sensitive to these carcinogens than laboratory rodents (Lijinsky, 1999). A long-standing hypothesis in the epidemiology of gliomas is that NOC exposure may increase risk. Transplacental exposure to ethylnitrosourea, a nitrosamide, results in formation of brain tumors including gliomas in rodents and primates. The addition of vitamin C to the diet prevents tumor formation in this model. Human NOC exposure divides equally between exogenous and endogenous sources. Nitrosamines in tobacco (mainly sidestream smoke), cosmetics, automobile interiors, and cured meats are the best-established exogenous (environmental) sources of NOC exposure. Other sources include rubber products (baby pacifiers, bottle nipples) and certain drugs including antihistamines, diuretics, oral hypoglycemic agents, antibiotics, tranquilizers, and narcotics. N-nitrodiethanolamine, a carcinogen in animal models, occurs mainly as a contaminant in cosmetic products, soaps, shampoos, and hand lotions. Some environmental sources may contain both nitrosamines and nitrosamides. Endogenous formation of NOCs is a complex process that occurs in the stomach. This process is dependent upon the presence of NOC precursors (i.e., nitrates and nitrites), gastric pH, the presence of bacteria, and other physiological parameters.

Measurement of NOC exposure is difficult, given the many exogenous and endogenous sources. Thus, misclassification of exposure is a major limitation for any study on this topic. However, because processed and cured meats are sources of NOC precursors and some preformed nitrosamines, dietary assessment may serve as a useful surrogate marker for NOC exposure.

Epidemiological support for NOC exposure as a risk factor for brain tumors comes mostly from studies of pediatric brain tumors and maternal diet. Several studies have assessed the association between maternal diet and childhood brain tumor risk (Dietrich et al., 2005). A meta-analysis determined that frequent intake of processed meats during pregnancy was associated with an elevated risk of childhood brain tumors (RR 1.68; 95% CI, 1.30-2.17) (Huncharek et al., 2003). However, the authors of this meta-analysis warn not to draw definitive conclusions, based on several study-design limitations such as recall bias and selection bias.

Case-control studies on dietary intakes of foods containing preformed nitrosamines or compounds that can be converted to nitrosamines yield inconsistent results. A few case-control studies reported strong positive associations (e.g., Blowers et al., 1997; Lee et al., 1997), but the potential for bias in these studies is high. A large prospective study with 335 incident cases of glioma examined meats and foods high in nitrites or nitrates and reported no increased risk for any of those foods (Michaud et al., 2009). Overall, despite some suggestion from experimental and observational data that NOC exposure may increase the risk of glioma, this hypothesis remains tenuous.

Vitamins

Vitamins C and E inhibit nitrosation reactions in vivo, and intake of these vitamins can reduce the endogenous formation of NOC in the stomach. Epidemiological studies have demonstrated that consumption of vitamin C reduces the risk of gastric cancer (La Vecchia and Franceschi, 2000), a tumor for which NOC may be a risk factor (Neugut et al., 1996). Statistically significant inverse associations with dietary vitamin C or supplemental intake have been observed in a few case-control studies. Furthermore, no associations were observed in a large prospective cohort study examining intakes of vitamins C, E, and a total antioxidant score and risk of glioma (Michaud et al., 2009). Currently, evidence does not support causation for vitamins and risk of glioma.

As with vitamin intake, findings on fruit and vegetable intake have been inconsistent. Inconsistent results for fruit, vegetable, and vitamin intakes are not surprising; in addition to the problems inherent in case-control designs, the initial design of several studies was not to test a dietary hypothesis. Consequently, most were limited in their ability to capture dietary exposures. Furthermore, the majority of studies on diet and gliomas have limited statistical power, making it difficult to draw conclusions from those findings. In a large prospective cohort study, fruit and vegetable intake, overall or within subgroups, was not associated with risk of glioma (Holick et al., 2007).

Tobacco and Alcohol

The presence of nitrosamines in tobacco smoke has stimulated interest in tobacco exposure as a potential risk factor for primary brain tumors. Several case-control and cohort studies have assessed the relationship between cigarette smoking and the risk of adult glioma; few have reported any positive association with cigarette smoking. Overall, the 2004 Surgeon General’s Report on the Health Consequences of Smoking concluded that “the evidence is suggestive of no causal relationship between smoking cigarettes and brain cancer in men and women” (U.S. Department of Health and Human Services, 2004). Findings from studies of maternal smoking (active and passive) and risk of primary brain tumors in offspring have been inconsistent, but overall the data do not support an increase in brain tumor risk with maternal smoking (Norman et al., 1996).

Because beer and liquor contain nitrosamines, speculation that consumption of alcoholic beverages may increase the risk of brain tumors exists. However, no consistent association is demonstrable between consumption of different types of alcoholic beverages and the risk of gliomas or meningiomas in childhood (maternal consumption) or adulthood.

Allergies

A consistent pattern of an inverse relationship between allergies such as asthma or eczema and the risk of glioma has emerged from observational studies. Although this association may not have any direct clinical or preventive implications, it may shed some light on mechanisms and the role of the immune system in the pathogenesis of primary brain tumors. Several plausible biological mechanisms exist that could explain the role of allergies. Although complex, most relate to the immune system response and the tendency for individuals with allergies to mount a stronger type 2 response.

In a meta-analysis based on 3450 cases of glioma, a 39% decrease in risk of glioma was observed among those reporting any form of allergy (RR 0.61; 95% CI, 0.55-0.67); the association was similar for asthma or eczema (Linos et al., 2007). The association is weaker for meningiomas.

Two studies focused on allergies to specific exposures (e.g., medicine, foods) and reported inverse associations for most types of allergies (Brenner et al., 2002; Wiemels et al., 2002). In one of these studies (Brenner et al., 2002), self-report of any type of allergy was associated with a 33% reduction in the risk of glioma (OR 0.67), and the OR for individual allergies ranged from 0.23 (allergy to chemicals) to 0.97 (hay fever). In the other study (Wiemels et al., 2002), a dose-response relationship was observed between increasing numbers of specific allergens and risk of glioma, with an OR of 0.37 for five or more described allergens compared to none.

In a case-control study (Wiemels et al., 2004), measures of biological markers of allergies reduced the bias that arises from self-reporting in a case-control setting and increased the specificity of exposure assessment. Serum samples collected from 226 adult glioma cases and 289 age-gender-ethnicity frequency-matched controls measured immunoglobulin (Ig)E, a clinical marker of atopic allergies. Compared to normal levels (<25 kU/L), individuals with elevated IgE levels (>100 kU/L) had an OR of 0.37 (95% CI, 0.22-0.64), and individuals with intermediate IgE levels (25-100 kU/L) had an OR of 0.64 (95% CI, 0.42-0.96) for glioma risk. Chemotherapy, radiation, surgery, and medication use (including nonsteroidal antiinflammatory drugs, allergy drugs, steroids, and antibiotics) did not affect IgE levels in cases or controls in this study. A similar finding was observable in a follow-up study on IgE levels and risk of glioma, although the association was weaker than in the first study, and drug treatment might have been a confounding factor (Wiemels et al., 2009).

The high degree of consistency in all reports, despite differences in study design (hospital, friend, and population controls), percentage of proxy interviews, and geographical location of the study, suggests that an etiological basis for allergies may exist. Moreover, the fact that allergy was not a risk factor for meningioma in most studies (Brenner et al., 2002; Schlehofer et al., 1999) argues against bias as being responsible for the inverse association with glioma risk.

Infections

The detection of viruses and virus-like particles in brain tumor specimens has resulted in speculation that viral infections may be involved in brain tumor development. Interest in simian virus 40 (SV40), a polyomavirus, was stimulated by animal studies documenting brain tumor development after intracerebral inoculation with SV40 and human studies in which SV40 was isolated from brain tumor tissue. Accidental contamination of administered poliomyelitis vaccine with SV40 occurred between 1955 and 1962. Follow-up studies of these vaccinated individuals did not find an overall increase in the risk of brain tumors (Engels, 2005). Furthermore, no significant association was observed between antibodies to SV40 (or two other polyomaviruses, JC virus and BK virus) and primary malignant brain tumors when measured directly in serum collected prior to cancer diagnosis (Rollison et al., 2003).

Several studies have suggested that certain infections may reduce the risk of adult glioma. In one study (Schlehofer et al., 1999), subjects who reported a history of infectious diseases (e.g., colds, flu) had a 30% reduction in risk (RR 0.72; 95% CI, 0.61-0.85) compared to those with no such history. A possible protective role for antecedent infection with chickenpox (varicella-zoster virus) reported in two different case-control studies used a self-report and serological measures of the antibodies to varicella-zoster virus (Wrensch et al., 1997, 2001, 2005). In one analysis of 229 adults with glioma and 289 controls, individuals with a history of chickenpox had a lower risk of glioma (OR 0.59; 95% CI, 0.40-0.86), and individuals with higher levels of immunoglobulin directed against varicella-zoster virus were at lower risk of glioma (OR 0.41; 95% CI, 0.24-0.70, comparing highest to lowest quartile of serological IgG) (Wrensch et al., 2005). Similar associations were not seen with three other herpesviruses (Epstein-Barr virus, cytomegalovirus, and herpes simplex virus) (Wrensch et al., 2001, 2005).

At the present time, epidemiological evidence implicating infectious agents as important factors in the etiology of brain tumors is inconclusive. However, a history of certain infections appears to relate inversely to brain tumor risk, and this association may, as with allergies, be mediated through the immune system.

Genetic Syndromes

Genetic syndromes that increase the risk of nervous system tumors cause approximately 1% to 5% of brain tumors (Kleihues et al., 2000). Neurofibromatosis type 1 (NF1; see Chapter 65) occurs in 1 in 4000 newborns and is linked to a gene on chromosome 17. Approximately 5% to 10% of persons with NF1 develop brain tumors, including malignant peripheral nerve sheath tumors, pilocytic astrocytomas of the optic nerve, and other astrocytomas. Neurofibromatosis type 2 (NF2) occurs in 1 in 40,000 newborns and has a corresponding link to a gene on chromosome 22. The presence of bilateral acoustic neuromas is the defining feature. Astrocytomas and other brain tumor types occur.

The Li-Fraumeni syndrome, an autosomal dominant condition, may involve a mutation in the tumor suppressor gene TP53, conferring an increased risk of soft-tissue sarcomas, osteosarcomas, breast cancer, and brain tumors. Approximately 12% of cancers in families with TP53 germline mutations are brain tumors; astrocytomas are the predominant type (Kleihues et al., 1997). Turcot syndrome is associated with adenomatous polyps and increased risk of medulloblastoma and glioblastoma. Persons with nevoid basal cell carcinoma (Gorlin syndrome) and Wilms tumor have an increased risk of medulloblastoma. Table 52A.1 summarizes inherited syndromes associated with an increased risk of nervous system tumors.

Familial clustering of brain tumors is also recognized outside of these defined syndromes. The chance of having a family member with a brain tumor is twice as high in adult brain tumor patients (8%) as in controls (4%). This familial clustering is greater for children and certain histological types of brain tumors (medulloblastoma). Although genetic syndromes account for only a small fraction of brain tumors in the United States, further study of the affected genes may provide insight into the molecular pathogenesis of sporadic brain tumors.

Genetic Polymorphisms

Recently, researchers have focused on genetic factors of brain cancers as a result of the increased availability of new technologies that allow rapid, effective, and affordable measurement of thousands of genetic variants. Genome-wide association studies (GWAS) involve the analysis of genetic variants in the whole genome and their relation to disease onset. Several GWAS have been conducted for glioma, providing new clues into possible genetic regions that may play a role in this disease. In one study, 5 susceptibility loci in genes TERT, CCDC26, CDKN2A/CDKN2B, RTEL1, and PHLDB1 were identified by genotyping 550K tagging single-nucleotide polymorphisms (SNPs) in a total of 2545 glioma cases and 2953 controls (Shete et al., 2009). In another study, the identification of 2 susceptibility loci (CDKN2B and RTEL1) was based on the analysis of 275,895 SNPs in 692 adult high-grade glioma cases and 174 controls (Wrensch et al., 2009). More GWAS currently underway may reveal additional new genetic regions important for glioma. Genetic polymorphisms in specific detoxification/metabolic enzymes have been implicated in the pathogenesis of certain cancers. The association between chemical carcinogens and brain tumors in experimental models raises the possibility that susceptibility may be related to genetic polymorphisms at loci encoding phase I cytochrome P450 (CYP450) and phase II glutathione S-transferase (GST) enzymes. Several potential neurocarcinogens (polycyclic aromatic hydrocarbons, nitrosoureas, and methyl halide) are substrates for these enzymes. Several case-control studies of brain tumors have assessed polymorphic enzymes (e.g., GSTT1, GSTM1, GSTP1, CYP2D6, NAT2, HRAS1) implicated in the activation or detoxification of potential neurocarcinogens; results from these studies are inconsistent. A meta-analysis of eight studies concluded that no evidence exists for an association between GST variants and risk of glioma (Lai et al. 2005). Other studies have been conducted on genetic polymorphisms involved in DNA repair, immune function, inflammation and allergies; results from these studies need to be replicated.