Brain and Central Nervous System Tumors☆

Brain and Central Nervous System Tumors☆ QT Ostrom, Case Western Reserve University School of Medicine, Cleveland, OH, USA ML Bondy, Baylor College of Medicine, Houston, TX, USA JS Barnholtz-Sloan, Case Western Reserve University School of Medicine, Cleveland, OH, USA ã 2015 Elsevier Inc. All rights reserved.

Introduction Congenital Conditions Familial Associations and Family History of Brain and CNS Tumors Genetic Susceptibility Heritable Variants Etiology and Risk Factors for Brain and CNS Tumors Ionizing Radiation Electromagnetic Fields Allergies Diet Industry and Occupation Viruses Drugs and Medications Cellular Telephones Conclusions References

Glossary Brain and CNS tumors Brain and CNS tumors are tumors that grow in the brain and/or CNS and can be either benign or malignant. A benign brain tumor consists of benign (harmless) cells and has distinct boundaries, but may occur in a vital area of the brain and be malignant. A malignant brain tumor is life-threatening, has uncontrolled growth, and poor prognosis. Glioma The general term for a tumor that arises from the supportive tissue of the brain (glial cells). Approximately

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90% of brain tumors are gliomas. Examples of these include astrocytoma, oligodendroglioma, and glioblastoma multiforme. Hereditary syndrome An inherited condition (or new mutation) that predisposes an individual to developing a brain tumor. Some of these syndromes include neurofibromatosis, tuberous sclerosis, and Turcot’s syndrome.

Introduction Environmental concerns, media, and questionable research methodologies complicate progress toward understanding the etiology of brain cancer and obscure the truism that, at the molecular level, all cancer is genetic. We review putative risk studies, which point to a need for genetic epidemiology, with sensitive statistical methods as the best hope for an explanation of brain cancer etiology. Brain tumors account for approximately 1.4% of all cancers and 2.4% of cancer deaths as reported by Siegel et al. (2014). These tumors are never truly benign, as slight impairments of brain or central nervous system (CNS) function from either cancer or its treatment can have dramatic consequence and cause significant morbidity. Primary brain tumors are currently classified according to the World Health Organization (WHO) classification of tumors of the central nervous system, as presented in Louis et al. (2007), in a manner that reflects their histological appearance and location. Gliomas arise from the glial tissues, accounting for 40% of CNS neoplasms, as reported in Ostrom et al. (2013), and is a general category that includes astrocytomas, oligodendrogliomas, and ependymomas. According to the WHO, there are four major grades of astrocytoma so denoted by their cellular star-like appearance and the most invasive of the tumors in children and adults. Grade I astrocytomas – or pilocytic astrocytomas – are the most frequently occurring brain tumors in children. These tumors rarely undergo neoplastic transformation or exhibit malignant behavior. Grade II astrocytomas account for 10% of all gliomas and are infiltrative in nature. Grade III or anaplastic astrocytomas are highly malignant gliomas and have an increased tendency to ☆

Change History: September 2014. Q Ostrom and J Barnholtz-Sloan updated all sections including updated references. Sections removed include: CNS Tumors among Twins, CNS Tumors among Siblings, CNS Tumors and Cancer Family Syndrome, Metabolic Susceptibility, Mutagen Sensitivity, and Chromosome Instability. Sections added include: Heritable variants, and Allergies.

Reference Module in Biomedical Research

http://dx.doi.org/10.1016/B978-0-12-801238-3.04290-2

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progress to glioblastoma. Grade IV astrocytoma or glioblastoma is a highly malignant brain tumor and typically affects adults. Glioblastoma is the most common type of malignant brain tumor, representing approximately 54% of gliomas and 16% of all brain tumors. This type of glioma has poor prognosis, with median survival of 12–14 months when treated with chemoradiation as reported in Stupp et al. (2005). Oligodendrogliomas account for less than 2% of intracranial tumors, and approximately 6% of gliomas. Oligodendrogliomas take their name and arise from the oligodendrocytes in the brain. Oligodendrogliomas are less aggressive than astrocytomas but are invasive and can traverse the cerebral spinal fluid (CSF). The ability of oligodendrogliomas to metastasize complicates their surgical removal, but because they are limited to the brain and CSF, some patients have a better prognosis and longer survival. Ependymomas are tumors arising from cells lining the brain ventricles or ependymal cells and account for approximately 7% of gliomas. Their growth may block the flow of CSF, causing notable swelling of the ventricle or hydrocephalus. Although ependymomas may move along the CSF, they characteristically do not infiltrate normal brain tissue and are sometimes amenable to surgical treatment, especially surgery of the spinal cord. Meningiomas arise from the sheaths surrounding the brain. The growth of meningiomas and the pressure they produce lead to the symptoms of brain tumors. Meningiomas are quite common, accounting for about 36% of primary central nervous system tumors. Because meningiomas are usually near the surface of the brain, they are often operable and are usually benign. Embryonal tumors are one of the most common types of primary brain tumors in children, where they account for approximately 16% of tumors in those <15 years old. These tumors are thought to derive from embryonic cells that remain in the central nervous system after birth. There are three major tumor types within this grouping: primitive neuroectodermal tumors (PNET), medulloblastoma, and atypical teratoid/rhabdoid tumors (ATRT). Medulloblastomas are the most common embryonal tumor, and arise primarily in the cerebellum. Molecular analysis of medulloblastoma has identified four distinct subtypes that correlate strongly with survival and treatment response. PNET are tumors that are histologically similar to medulloblastoma but occur supratentorially as opposed to infratentorially. Prior to the 1993 WHO CNS histology criteria, these tumors were considered PNET regardless of tumor location. ATRT is a rare embryonal tumor that most commonly occurs in children <3 years old that is highly malignant. This diagnostic category was created with the 2000 WHO CNS histology revision. Schwannomas (neurilemomas) arise from Schwann cells, which surround cranial and other nerves. Schwannomas are usually benign tumors and often form near the cerebellum and in the cranial nerves responsible for hearing and balance. Chordomas are spinal tumors that preferentially arise at the extremities of the spinal column and usually do not invade brain tissues and other organs. They are amenable to treatment but stubbornly recur over a span of 10–20 years. Geneticists, molecular biologists, and epidemiologists are seeking methods for identifying and characterizing brain tumor genes for a clearer understanding of cancer etiology and to develop prevention strategies. Of special interest in carcinogenesis are protooncogenes, initiating carcinogenesis by activating cell division, and suppressor genes, inhibiting tumors. Epigenetic processes may also inhibit or stimulate tumor growth. Equally essential information under scrutiny is the mechanism of gene–environment and gene-gene interactions. Guiding characterization and gene–environment investigations are studies of known heritable syndromes associated with CNS tumors. These studies also indicate the potential of further collection and use of genetic data.

Congenital Conditions Brain tumors are associated with several hereditary tumor-associated syndromes, as well as other congenital abnormalities that may point to potential genetic abnormalities associated with brain tumors. Original studies of CNS tumor-associated syndromes, as well as hereditary conditions associated with CNS tumors, parallel in method and implication the studies of other congenital anomalies. These associate congenital medulloblastoma with gastrointestinal and genitourinary system anomalies, congenital ependymoma with multisystem anomalies, astrocytoma with arteriovenous malformation of the overlying meninges, and glioblastoma multiforme with adjacent arteriovenous angiomatous malformation and pulmonary arteriovenous fistula. CNS tumors commonly arise in individuals with Down’s syndrome, a disorder involving trisomy 21, and gliomatous tumors with syringomyelia, a disorder possibly of genetic origin. Mental retardation may also be associated with familial brain cancer, as children with astrocytomas had a mentally retarded sibling three times more frequently than controls (p ¼ 0.04), whereas mentally retarded sibs, nieces, and nephews occurred in families of adult males 4.8 times more often than in families of controls. Agha et al. (2005) report a 2.5 fold increase in CNS cancer risk among those with congenital abnormalities in Ontario, which increases to 5.5 fold increased risk when looking only at children <1 year old. Studies of the California birth defects monitoring system have supported these results. Approximately 5% of brain tumors can be attributed to hereditary cancer syndromes. These syndromes are described briefly here, and in more detail in Farrell and Plotkin (2007). Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited progressive disorder occurring in 1 per 6,000 live births TSC is heterogeneous and can be attributed to gene abnormalities on chromosomes 9q34 (TSC1) and 16p13 (TSC2). Approximately 70% of reported cases are sporadic, but these sporadic cases present with rates of TSC2 mutation at a higher rate than expected and are often more severe clinically. It is characterized by hamartomas and hamartias of the skin, CNS, and kidneys and results in sebaceous adenomas of the skin, muscle and retinal tumors, epileptic seizures, mental retardation, and nodes or tubers of abnormal glial fibers and ganglion cells in the brain. Lesions including cortical

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tumors, subependymal modules, and subependymal giant cell astrocytomas (SEGA) are common in those with TSC. Approximately 5–15% of persons with TSC develop SEGA. Neurofibromatosis (NF-1) – also called von Recklinghausen’s disease or peripheral neurofibromatosis, occurs in approximately 1 of 3,000–4,000 live births. NF-1 has an autosomal-dominant pattern of heredity, and is regarded as among the most common single gene disorders. About half of persons with NF-1 have sporadic mutations and unaffected parents. The NF-1 locus maps to 17q11.2. NF-1 characteristics are cutaneous pigmentation (cafe-au-lait spots) and multiple neurofibromas involving the skin and possibly deeper peripheral nerves and neural roots. NF-1 patients (94%) present with Lisch nodules or pigmented iris hamartomas and commonly experience optic nerve gliomas, astrocytomas, ependymomas, acoustic neuromas, neurilemmomas, meningiomas, and neurofibromas. Of NF-1 patients, 4–45% experience brain tumors. Neurofibromatosis type 2 (NF-2) – also known as central neurofibromatisis, or or bilateral acoustic neurofibromatosis – occurs in approximately 1 in 25 000-40 000, about one-tenth the frequency of NF-1. NF-2 is caused by a deletion in the long arm chromosome 22. The protein produced by NF-2 functions as a tumor suppressor, and loss of this gene is common in sporadic schwannomas and meningiomas that occur in persons without NF-2. Brain tumors associated with NF-2 include: vestibular schwannomas of the cranial nerves (occurring in nearly all patients) spinal schwannomas, meningilmas (50% have intracranial, 4–8% have optic sheath tumors), spinal ependymomas and astrocytomas (approximately 53% of patients). These tumors are usually non-malignant or low grade tumors, but can have devastating neurological effects as well as severe morbidity. Gorlin’s syndrome – also called nevoid basal cell carcinoma syndrome – is an autosomal-dominant disorder that occurs in approximately 1 in 57 000–164 000. Gorlin’s syndrome occurs in the absence of a family history approximately 50% of the time. It is linked to germline mutation of Patched (PTCH) on chromosome 9q. It commonly presents with multiple basal cell carcinomas having arisen early in life and jaw cysts, characteristic facies, skeletal anomalies, intracranial calcifications of the falx, and ovarian fibromas. Lifetime risk of developing a medulloblastoma is 5% in persons with Gorlin’s, and approximately 2% of persons with medulloblastoma are found to have Gorlin’s. Turcot’s syndrome refers to the association of brain tumors and colorectal polyposis. It is characterized by one of two forms of hereditary color cancer: familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC). FAP is associated with mutations in the adenomatosis polyposis coli (APC) gene on chromosome 5 and HNPCC patients have mutations in a series of DNA-mismatch repair genes (including hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6). Brain tumors are common in families with FAP, where approximately 60% have medulloblastomas, 14% have astrocytomas, and 10% have ependymomas. In families with HNPCC, affected patients have increased incidence of gliomas including glioblastoma. Sturge–Weber disease is an inherited neurocutaneous syndrome that occurs sporadically, and is caused by a mutation in guanine nucleotide binding protein, q polypeptide (GNAQ). It is characterized by facial and leptomeningeal angiomas and, facial and optical port wine lesions. Computer-assisted tomography (CT) and magnetic resonance imaging (MRI) of Sturge–Weber cases show cerebral lobar atrophy, brain calcification, choroid plexus enlargement, and venous abnormalities. Von Hippel–Lindau disease is a rare autosomal dominant multisystem disorder that occurs in approximately 1 in 31 000–39 000 live births. The disease is linked to a mutation in von Hippel-Lindau tumor suppressor (VHL) on the short arm of chromosome 3. Presentation of this disease involves cerebellar hemangioblastoma of the CNS and visceral organs, retinal angiomatosis, pancreatic cysts, and benign and malignant renal lesions. Recent studies have suggested that 20–38% of cerebellar hemangioblastomas are associated with Von-Hippel Lindau, and 15% of persons also develop tumors of the endolymphatic sac within the temporal bone. A syndrome first described by Li and Fraumeni in 1969 showing a familial association of breast cancer, sarcoma, leukemia, and brain tumors. It has been shown that this association is vertically transmitted in a dominantly inherited pattern. Germline p53 mutations have also been identified with this syndrome.

Familial Associations and Family History of Brain and CNS Tumors In addition to the association of hereditary syndromes with CNS tumors, investigation of brain cancer etiology focuses on families of CNS tumor patients aggregating CNS and other cancers. Methodologic constraints unfortunately limit the authority of many of these studies, also obscured by the confounding factor of common familial exposure to environmental agents potentially contributing to neoplasia induction. Linkage studies conducted within families by Shete et al. (2011) and Sun et al. (2012) containing multiple affected members have had little success identifying high-penetrance glioma risk variants. Results of studies looking at risk of CNS tumors within families that are not associated with hereditary cancer syndromes have varied substantially. In a review of these studies, Dearlove et al. (2008) concluded that most of these found not significant increase in cancer risk among family members of children with brain tumor, but siblings of children with CNS tumors consistently have an increased risk of developing a CNS tumors. This risk is higher if the child has an embryonal tumor, or if the tumor was developing at a younger age. Searles Nielsen et al. (2008) reported the results of the SEARCH international case control study after Dearlove et al.’s review, which found no significant association between childhood brain tumors and history of brain tumors in close relatives. Sadetzki et al. (2013) reported results from the Gliogene Consortium which showed that familial cases of CNS tumors are most often clusters of two individuals within a family, suggesting that any familial trait that increases glioma risk has low penetrance.

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Genetic Susceptibility Heritable Variants Gliomas are the brain tumor type that has undergone the most comprehensive genetic interrogation. In the absence of a clear pattern of risk variants, segregation analyses have determined that genetic risk factors for glioma are best explained with a polygenic model in de Andrade et al. (2001). Results from genome-wide association studies (GWAS) have supported this conclusion by identifying common genetic variation in seven genes which increase glioma risk. Until recently, most of the studies assessing genetic variants associated with risk of glioma were candidate gene studies, focusing on genes thought to be involved in gliomagenesis. Since advances in technology that now allow for rapid whole genome genotyping, five genome-wide association studies (GWAS) of glioma patients have been conducted: Shete et al. (2009), Wrensch et al. (2009), Chen et al. (2011), Sanson et al. (2011), Rajaraman et al. (2012). Together these studies identified seven genomic variants that increased glioma risk. The variants and their respective genes are: telomerase reverse transcriptase (TERT, rs2736100), epidermal growth factor receptor (EGFR, rs2252586 and rs11979158), coiled-coil domain containing 26 (CCDC26, rs55705857), cyclin-dependent kinase inhibitor 2B (CDKN2B, rs1412829), pleckstrin homology-like domain, family B, member 1 (PHLDB1, rs498872), tumor protein p53 (TP53, rs78378222), and regulator of telomere elongation helicase (RTEL1, rs6010620). Four of these variants (TERT, RTEL1, EGFR, and TP53) increase risk of all types of glioma, while three only increase risk for specific grades, and histologies (CDKN2B, PHLDB1, and CCDC26). Both CCDC26 and PHLDB1 are associated with isocitrate dehydrogenase 1/2 (IDH 1/2)-mutant tumors (predominately WHO grade II and III gliomas), whereas CDKN2B is associated with astrocytic tumors in general, WHO grades II to IV. Two of the variants that increase risk for all glioma types are in telomere-related genes (rs2736100 [TERT] and rs6010620 [RTEL1]). Telomere length has been associated with other types of cancer, but a recent case-control study conducted by Walcott et al. (2013) has not found a significant overall association between this variant and risk of glioma. In contrast, Walsh et al. (2014) and Bainbridge et al. (In Press) report a significant association between germline mutations in the TERT and protection of telomeres 1 (POT1) genes, telomere length, and glioma risk. The risk variants within these genes are more common among those with older age at diagnosis with glioma, which suggests that this telomere-based pathway may be a distinct mechanism of gliomagenesis. Inherited mutations in TP53 contribute to the development of Li-Fraumeni syndrome, and the mechanism for its contribution to gliomagenesis is well understood, as reported in Enciso-Mora et al. (2013). The risk allele identified via GWAS (rs78378222) in TP53 is rare in the general control population (<1%) and having this variant confers a 3 increase in risk for glioma. EGFR, TP53, TERT, and CDKN2A/B are genes that often acquire somatic changes during gliomagenesis, but more research is necessary to understand the relationship between germline and somatic changes in glioma. Medulloblastoma has undergone significant omic study, and microarray expression profiling has produced 4 distinct subgroups that robustly predict treatment response and survival, as reported by Kool et al. (2012). These groups include WNT (10% of cases), sonic hedgehog (SHH) (30%), Group 3 (25%), and Group 4 (35%). WNT tumors have the highest overall 5 year survival (95%) and are characterized by loss of chromosome 6, and mutations in catenin (cadherin-associated protein), beta 1 (CTNNB1), DEAD (Asp-Glu-Ala-Asp) box helicase 3, X-linked (DDX3X), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), lysine (K)-specific methyltransferase 2D (MLL2), and TP53. Children with SHH tumors are the most common type of medulloblastoma in infants, and have 75% 5 year overall survival. These tumors are characterized by gains in chromosomes 3q and 9p, and losses in 9q, 10q,14q, and 17q, as well as mutations in patched 1 (PTCH1), TP53, MLL2, DDX3X, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), BCL6 corepressor (BCOR), LIM domain binding 1 (LDB1), transcription factor 4 (TCG4), GLI family zinc finger 2 (GLI2). Group 4 tumors are most common in mid-to-late childhood, and have 57% 5 year overall survival. These tumors are characterized by gain in chromosomes 4, 7, 17q, and 18, as well as losses in 8, 10, 11, and 17p. Characteristic mutations include lysine (K)-specific demethylase 6A (KDM6A), synuclein, alpha interacting protein (SNCAIP), v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), lysine (K)-specific methyltransferase 2C (MLL3), cyclin-dependent kinase 6 (CDK6), and zinc finger, MYM-type 3 (ZMYM3). Group 3 tumors have the poorest overall 5 year survival (50%), and are characterized by gains in chromosomes 1q, 7, 17q, and 10, as well as losses in 8, 10q, 11, 16q, and 17p. These tumors are characterized by mutations in v-myc avian myelocytomatosis viral oncogene homolog (MYC), Pvt1 oncogene (non-protein coding) (PVT1), SMARCA4, orthodenticle homeobox 2 (OTX2), CTD nuclear envelope phosphatase 1 (CTDNEP1), low density lipoprotein receptor-related protein 1B (LRP1B), and MLL2. As genomic technologies continue to evolve and become most cost effective, genomic analysis and characterization of brain tumors will continue to garner more information and be applied to a wide variety of histological types of brain and CNS tumors.

Etiology and Risk Factors for Brain and CNS Tumors Ionizing Radiation Research consensus holds that therapeutic ionizing radiation is a strong risk factor for intracranial tumors. Even relatively low doses (averaging 1.5 Gy) for ringworm of the scalp (tinea capitis) have been associated with relative risks of 18, 10, and 3 for nerve sheath

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tumors, meningiomas, and gliomas, respectively, as reported by Sadetzki et al. (2005). Other studies report a prevalence of prior therapeutic radiation among (17%) patients with glioblastoma or glioma and increased risk of brain tumors in children after radiation for acute lymphoblastic leukemia. The role of diagnostic radiation exposures in the development of brain tumors is still unclear. Two studies, by Preston-Martin et al. (1989) and Davis et al. (2011), have demonstrated increased risk of glioma after 3 or more cumulative CT scans to the head only in persons with a family history of cancer, and two recent cohort studies of children experiencing CT scans in Britain by Pearce et al. (2012) and Australia by Mathews et al. (2013) have suggested increases in cancer, including brain cancer, after childhood exposures to CT scans. There have been significant increases in per capita doses of diagnostic radiation in the last two decades, and as a result this requires further investigation. A recent consensus of radiation experts, Linet et al. (2012), concluded that there is good evidence of increased cancer at x-ray or gamma radiation doses of about 10 to 50 mSv. Risk due to prenatal or occupational radiation exposure remains unknown, as studies of in utero exposure to atomic bomb or occupational radiation have found standard brain tumor incidence or results that are confounded or contradictory. Small-scale prenatal exposure studies are statistically insignificant, and the slightly elevated risk associated with a comparatively uncommon radiation exposure would not explain most childhood brain tumors. The study finding a small but statistically significant elevated risk of 1.2 for brain tumors in nuclear facility employees and nuclear materials production workers allows for the possibility of confounding or effect modification by chemical exposures. A study by Yong et al. (2014) reporting increased mortality from brain tumors among airline pilots, possibly implicating exposure to cosmic radiation at high altitudes, is contradicted by another study by Hammer et al. (2014) reporting standard morbidity rates in pilots.

Electromagnetic Fields The possible association between exposure to extremely low-frequency magnetic fields (ELF) and brain tumors has been examined over several decades. Despite largely negative findings, debate over the impact of electromagnetic fields on brain cancer continues, prolonged by methodological difficulties with some studies and popular media warnings about consumer products inviting personal exposures. Wertheimer and Leeper (1979) described an apparent increased risk of brain tumors and leukemia in Denver children living near high-current versus low-current wiring. Their report set off widespread public and scientific interest in the potential health effects of electromagnetic fields and electronic devices, but positive findings came into question after contrary outcomes and reviews of sample sizes and methods. Among the studies reducing suspicion about electricity was a meta-analysis showing an insignificant increased childhood brain tumor risk for residents in homes coded for high current. In a meta-analysis of 48 studies of adult brain tumors in relation to occupational exposures to electric and magnetic fields, apparently adding to the weight of evidence against electricity, Kheifets et al. (2008) reported a significant (10%) increased risk for brain cancer among electrical workers, but there was no consistent doseresponse relationship. Two large cohort studies by Roosli et al. (2007) and Koeman et al. (2014) have found no differences in risk of brain tumor with occupational ELF exposure. Electromagnetic field (EMF) investigation continues in the quest of reliable risk determination, but exposure research reveals inconsistencies. EMF measurement in the home is inexact because of varying wire codes and the spot measurement snapshots usually taken for studies and, as well, the neglect of long-term exposure measurement or factoring in additional potential exposures from internal wiring, appliances, and gadgets. Temporal, intensity, and external influences may overshadow domestic exposures. The difficulties of quantification in EMF research pale compared to the main problem in this field of investigation: electromagnetic fields are incapable of inducing mutations that in turn might promote tumorigenesis. The EMF studies, as well as several occupational or environmental reports, and many cluster reports, lack the criteria for causal relationships proposed by Bradford Hill, among which are specificity, temporality, dose-response, consistency, and biologic plausibility.

Allergies Epidemiologic studies consistently suggest that allergic and atopic conditions – including asthma, hay fever, eczema and food allergies – consistently reduce glioma risk. This association has also been found by Turner et al. (2013) in other tumor types, including meningioma, vestibular schwannoma, and parotid gland tumors. Results from a meta-analysis conducted by Linos et al. (2007) reveal that allergies reduce glioma risk by nearly 40%. Studies have shown that glioma patients have lower levels of immunioglobulin E (IgE), a biomarker of allergy. This supports the association found in previous analyses based on self-report. Use of prediagnostic serum IgE is ideal to address the problem of recall bias in patients reporting allergy history post-diagnosis, but these may potentially be affected by a developing tumor. Researchers have focused on germline SNPs in order to get at these differences in IgE in a manner that would not be affected by tumorigenesis. Investigators have therefore evaluated SNPs that play a role in IgE production or allergy (e.g., interleukin 13 [IL13], IL4, and IL4 receptor-alpha [IL4Ra]) to determine whether they were associated with glioma risk. Results of these studies are conflicting, but in a meta-analysis Sun et al. (2013) found that rs20541 [IL13] but not rs1801275 [IL4Ra] may be a genetic indicators of glioma risk. Schwartzbaum et al. (2010b) conducted a case-control study compared 911 immune function genes in germline DNA from two large independent studies and found an association in both data sets with the interleukin 2 receptor, alpha (CD25) gene. Schwartzbaum et al. (2010a) also studied expression of 919 allergy and inflammation-related genes and their association with

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an indicator of tumor aggressiveness (prominin 1 [CD133] expression) in glioblastoma tissue samples, and found that the more aggressive the tumor, the lower the expression of the majority of allergy- and inflammation-related genes.

Diet Studies of the susceptibility of primates and other mammals to chemically induced brain tumors have prompted extensive study of diet and brain tumors. Experimental animal studies find N-nitroso compounds are clearly neurocarcinogens; other investigations describe mechanisms involving DNA damage through which N-nitroso compounds might cause brain tumors. These compounds can initiate neurocarcinogenesis through both prenatal and postnatal exposure, although in animals, more tumors result from fetal than postnatal exposures. However, the ubiquity of N-nitroso compounds complicates human dietary studies. N-nitroso compounds arise in the digestive system in a promoting enzymatic milieu when common amino compounds from fish, other foods, or drugs contact a nitrosating agent, such as nitrites in cured meats. Some vegetables also contain nitrates convertible to nitrites but also contain vitamins that block the formation of N-nitroso compounds. Human diet studies have achieved no consensus for hypothesis that dietary N-nitroso compounds heighten the risk of both childhood and adult brain tumors. However, a recent study by Searles Nielsen et al. (2011) found that risk of childhood brain tumor increased when mothers had consumed more cured meat than controls only when the fetus had a genetic polymorphism in a gene coding for glutathion S-transferase, which may inactivate nitroso compounds. Two large cohort studies, Michaud et al. (2009) and Dubrow et al. (2010), have found no link between consumption of dietary nitrites or nitrates and risk of glioma in adults. Numerous studies have examined the potential relationship between alcohol, tobacco and brain tumors, but despite much searching neither has been clearly implicated as a risk factor. A recent meta-analysis by Galeone et al. (2013) found no increase in risk for brain tumor based on alcohol consumption. Despite its other dangers and the polycyclic aromatic hydrocarbons and nitroso compounds in its smoke, tobacco has not been established as a causative agent in primary brain tumors. A recent metaanalysis by Fan et al. (2013) found no increase in risk for meningioma based on smoking, and another recent analysis by Milne et al. (2013) have found no increase in odds of brain tumor for children whose parents smoked before or after birth. Even in the absence of definitive findings in human studies, the demonstrations of fetal genotoxicity from metabolites of tobacco smoke, and the demonstrable presence of adducts, should lead to strong recommendations for mothers to reduce fetal and infant exposure to tobacco smoke.

Industry and Occupation Linkages between specific chemicals and development brain tumors in specific occupational groups have been studied for years, resulting in inconsistent findings. These studies are complicated by small numbers and the difficulties of segregating one of the many agents in the workplace, as well as other inherent problems in retrospective studies. Chemical implantation shown to provoke tumors in animals differs from inhalation or dermal exposures in occupational settings, but findings from animal experiments may be inapplicable or irreproducible in humans. Follow-up studies of occupationally induced brain cancer usually consist of too few affected subjects to establish or pinpoint causal chemicals, physical agents, work processes, or interactions. In the Upper Midwest Health Study (UMHS), Ruder et al. (2012) developed, a priori, a list of 21 exposures of interest identified from the literature as being potentially related to glioma risk. These exposures ranged from pesticides (e.g. farmers, pesticide applicators) to lead (e.g. gasoline station attendants, plumbers) to polychlorinated biphenyls (e.g. electrical workers, construction workers) to N-nitroso compounds (e.g. rubber manufacturing workers). Of these 21 exposures, only exposure to raw meat and possible exposure to non-ionizing radiation were associated with an elevated risk of glioma. The INTEROCC study was a multi-center case control study that included study sties in 10 study sites in 7 countries (Australia, Canada, France, Germany, Israel, New Zealand and the United Kingdom) that sought to assess the relationship between development of brain tumors and selected occupational exposures estimated through job exposure matrices (JEM), which characterize assumed exposure based on job title and length of work. Selected exposures included solvents, combustion products, metals, and dusts, as well as formaldehyde and sulphur dioxide. None of the exposures selected showed any significant relationship to glioma with any of three different exposure indices, as reported in Lacourt et al. (2013). McLean et al. (2014) reported that no significant relationships were detected between the examined solvents and meningioma. Other studies have also found no significant relationships between chemical exposure and risk of either glioma or meningioma.

Viruses Certain viruses, like the suspect chemicals, have been found to induce brain tumors in animal studies. As in chemical studies, small numbers and negative findings hinder epidemiological evaluation. Repeatedly, calls have been made for aggressive studies addressing the role of viruses (and other infectious agents) in causing human brain tumors. Very few epidemiological studies have addressed the virus–tumor relationship. Viruses and infectious agents could be an explanation for a proportion of brain tumors, and therefore intriguing as virology advances. Contamination of the widely distributed Salk vaccine for polio by the simian virus 40 (SV40) offered the numbers from which to derive significant statistics, as 92 million United States residents received it. However investigations of SV40 were flawed, based on questionable recall or anecdote, or amenable to confounding factors. Generally no association between virus and cancer could

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be established, although it may not be ruled out because the level of contamination varied among lots and manufacturers and was not taken into account in the United States and in Germany. A minority of brain tumor specimens are found to be contaminated with SV40, as reviewed in Vilchez and Butel (2003). Viral disease investigations for protective or heightened risk effects are similarly contradictory. Bithell et al. (1973) reported that mothers of children with medulloblastoma were exposed in pregnancy to chicken pox (also known as varicella zoster), a herpes virus. Conversely, Wrensch and colleagues found that mothers of glioma cases had lower rates than controls of previous chicken pox or shingles. This observation was supported by serologic evidence that cases were less likely than controls to have antibody to varicella zoster virus, the agent for chicken pox and shingles. Adults with glioma have also been reported by Wrensch et al. (2005) to have lower levels of immunity to varicella-zoster. A recent study by Lee et al. (2013) found an interaction between a reported history of allergy and the presence of Varicella zoster antibodies in blood samples collected prior to diagnosis with glioma, which suggests the importance of immune function in gliomagenesis. The JC virus has come under scrutiny because it is excreted in the urine of immunosuppressed, immunodeficient, and pregnant women and was found associated with medulloblastoma in children and other tumors. However, the JC virus exists in cancer-free subjects and its connection, if any, to tumorigenesis is only a surmise. Cytomegalovirus (HCMV), a herpes virus, has been associated with brain tumors in some but not all studies. It has been discovered in a large percentage of primary medulloblastoma and medulloblastoma cell lines, as well as in high grade glioma samples. It has also been detected in a large portion of glioblastoma, anaplastic glioma, and low grade glioma as reported by Scheurer et al. (2008a). Some studies have also found infection with HCMV to be positively associated with survival in glioblastoma but this is not consistently reported. Amirian et al. (2013a) recently reported results from a case-control study that among those who had positive IgG for HCMV in post-diagnostic blood samples, increasing levels of anti-HCMV IgG were associated decreasing glioma risk. After adjusting for demographic factors, those with IgG levels <10 U/ml had 2.5 times the risk of developing a glioma than those with higher IgG. Conversely, in a case-control study using pre-diagnostic plasma samples from cases and controls Sjostrom et al. (2011) reported no significant increase in risk associated with seropositivity to HCMV. An analysis of glioblastoma and low grade glioma samples collected by the Cancer Genome Atlas (TCGA) by Amirian et al. (2014) found that a substantial portion of these samples had DNA sequences that aligned to the human herpesvirus 6A/B (HHV-6A/B) genome, and that an additional portion had sequences from HHV-6A/B present in both tumor and germline DNA. The potential effect of viruses on brain tumor development and prognosis is plausible, but as of yet unproven.

Drugs and Medications Preliminary studies have generally reported an insignificant association between tumors and medications, including pain, headache, sleep, fertility drugs, oral contraceptives, tranquilizers, antihistamines, and diuretics. There have also been inconsistent results reported for maternal medication usage and childhood brain tumors. Several types of brain tumors have significant differences in incidence between men and women. In particular, meningioma is significantly more common in women and gliomas are significantly more common in men. The potential effect of fertility drugs, hormonal replacement therapy, and oral contraceptives on brain tumor risk have been studied extensively. A recent meta-analysis by Qi et al. (2013a) of studies conducted prior to 2013 found an association between longer exposure to hormone replacement therapy and risk of meningioma. The group also conducted a meta-analysis of hormonal drug use in relation to glioma; Qi et al. (2013b) found a decreased risk of glioma for women who had ever used exogenous hormones in their analysis. Due to the protective effect of allergies against the development of brain tumors, significant study has been performed on the relationship between antihistamine use and brain tumor risk. While analyses by Scheurer et al. (2008b) and Amirian et al. (2013b) have demonstrated an increase in glioma risk with antihistamine use, some have found this effect only in those with previous history of allergy or asthma diagnosis. Expanded analyses by Scheurer et al. (2011) show that regular use of antihistamines increased glioma risk for only WHO grade III tumors, regardless of asthma or allergy history. Results from another analysis by McCarthy et al. (2011) suggest an inverse association between antihistamine use and high-grade glioma risk (WHO grade III-IV), but only among those with no medically diagnosed allergy. A meta-analysis conducted by Liu et al. (2013) of studies conducted between 2003 and 2013 found no association between non-steroidal anti-inflammatory (NSAID) use and risk of brain tumor. As NSAIDS is suggested to be protective against certain cancers – including colorectal cancer, ovarian cancer, and melanoma – the role of these drugs in brain tumors should be investigated.

Cellular Telephones Cellular phone technology was introduced in the 1980s, but became popular in the mid-1990s worldwide where currently the vast majority of people use cellular phones. The telephones contain a small transmitter that emits radio frequency radiation next to the head, and there has been great public concern that individuals exposed to radiation emitted from wireless communication technologies might have an increased risk of developing tumors of the brain and nervous system. Several large-scale case-control studies have examined reported cell phone usage patterns between persons with glioma and those without, and have found mixed results about the effect of cellular phone use on glioma risk. The International Agency for Research on Cancer (IARC) conducted a thorough evaluation of the epidemiological findings of this research and classified radiofrequency fields as a possible carcinogen

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(IARC group 2B) in 2011 Baan et al. (2011). This classification is largely due to findings published prior to this that demonstrate increased risk of brain tumors in heavy users (variably defined) of cellular phones. Also in 2011, the International Commission for Non-Ionizing Radiation Protection Standing Committee on Epidemiology reviewed the evidence presented by epidemiologic studies conducted up to that point – compiled in Swerdlow et al. (2011) – and found that the trend of these studies did not support a relationship between cellular phone exposure and glioma risk. Six studies examining the relationship between cellular phone use and glioma have been published since the IARC report: two cohort studies, one case-control study, and three studies comparing incidence rates over time. Both cohort studies used cellular phone subscription records (in Denmark and the United Kingdom) and found no increase in glioma risk, including those who had used cellular phones for longer than 10 years or daily phone use. In the first of these cohort studies, Frei et al. (2011) examined 358 403 persons (including 3,664 glioma cases) in Denmark that had subscribed to cellular phone service prior to 1995, and found no statistical significant risk for both men and women with use over 10 years (Men relative risk [RR] ¼ 1.0, 95% CI ¼ 0.8–1.3, Women RR ¼ 1.0, 95% CI ¼ 0.6–2.0). Using the UK million woman study cohort, Benson et al. (2013) analyzed 791 710 women between 50 and 64, and found no statistical significant risk with greater than 10 years of use (RR ¼ 0.8, 95% CI ¼ 0.5–1.1). A casecontrol study conducted by Hardell et al. (2013) using 593 malignant brain tumor cases and 1,368 controls found an increased risk for any use of cellular phone (Odds ratio [OR] ¼ 1.6, 95% CI ¼ 1.0–2.7) and increased odds for heavy users (>2,736 h of call time, OR ¼ 2.8, 95% CI 1.6–4.8). Surveillance of trends in incidence of brain tumors over time is also an important way to investigate the potential effect of cellular phone use on these tumors. There has been a rapid increase in the use of cellular phones since their introduction in the 1980s. Currently, the vast majority of people in the world use cellular phones. Three of these analyses have been published since 2011, looking at trends in the Nordic countries (Denmark, Finland, Norway and Sweden) by Deltour et al. (2012), the United States by Little et al. (2012), and Israel by Barchana et al. (2012). All of these showed no significant increases in the incidence rates of glioma. These studies also compared current incidence rates to those that would have occurred with the magnitude of risk reported by previous case-control studies, and found that current incidence rates were much lower than predicted. The scientific evidence used to produce the 2011 IARC report, as well as the scientific evidence reported since its publication does not support a significant association between use of cellular phones and risk of glioma. This exposure warrants continued monitoring and examination, as the potential risks of long-term heavy use, risk of use during childhood and adolescence, and length of glioma latency is not well understood.

Conclusions The most generally accepted model, and productive of the most fruitful research, of carcinogenesis holds that cancers develop through the accumulation of genetic alterations that allow the cells to escape regulatory mechanisms and/or destruction by the immune system. Some inherited alterations in crucial cell cycle control genes, such as p53, as well as chemical, physical, and biologic agents that damage DNA, are therefore considered candidate carcinogens. Although rapid advances in molecular biology, genetics, and virology promise to help elucidate the molecular causes of brain tumors, continued epidemiologic work will be necessary to clarify the relative roles of different mechanisms in the full scope of brain and CNS tumors. In summary, the etiology of brain tumors remains largely unknown. The only validated risk factors for brain tumors are radiation to the head (which increases risk) and allergies/atopic disease (which decreases risk), however exposure to these accounts for only a small proportion of brain and CNS tumors. In the continuing search for explanations for this devastating disease, new concepts about neurooncogenesis might emerge, making the study of brain tumor epidemiology particularly exciting. Until the gene or genes for brain tumors are identified, genetic counseling in families at high risk of brain tumors is not possible. However, individuals with specific hereditary syndromes that predispose to brain tumors can be appropriately counseled about their genetic risks.

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