Brain tumor biomarkers for research, clinics, and registries - The 2021 Brain Tumor Epidemiology Consortium meeting report.

The Brain Tumor Epidemiology Consortium (BTEC) is an international consortium that fosters interdisciplinary collaborations focusing on research related to the etiology, outcomes, and prevention of brain tumors. The 21st annual BTEC meeting with the theme "Brain Tumor Biomarkers for Research, Clinics, and Registries" was held virtually from June 22 to 24, 2021. Scientists from North America and Europe, representing a broad range of brain tumor research interests, presented recent research and progress in the field. The meeting content is summarized in the following report.

Brain tumor disparities: From biology to social determinants - The 2019 Brain Tumor Epidemiology Consortium meeting report.

The Brain Tumor Epidemiology Consortium (BTEC) is an international consortium that fosters international and interdisciplinary collaborations focusing on research related to the etiology, outcomes, and prevention of brain tumors. The 20th annual BTEC meeting with the theme "Brain tumor Disparities: From Biology to Social Determinants" was held in Los Angeles, CA, USA, on June 6 - 8, 2019. Scientists from the United States and Europe representing a broad range of brain tumor research disciplines presented their research findings at the meeting. The scientific content of the meeting is summarized below.

Advancing brain tumor epidemiology - multi-level integration and international collaboration: The 2018 Brain Tumor Epidemiology Consortium meeting report.

The Brain Tumor Epidemiology Consortium (BTEC) is an international consortium that aims to foster multicenter and inter-disciplinary collaborations that focus on research related to the etiology, outcomes, and prevention of brain tumors. The 19th annual BTEC meeting was held in Copenhagen, Denmark, on June 19 - 21, 2018. The meeting focused on forming international collaborations and integrating multiple data types for the next generation of studies in brain tumor epidemiology. The next BTEC meeting will be held in Southern California in June 2019.
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Brain tumor epidemiology in the era of precision medicine: The 2017 Brain Tumor Epidemiology Consortium meeting report.

The Brain Tumor Epidemiology Consortium (BTEC) is an international consortium that aims to advance the development of multicenter and interdisciplinary collaborations that focus on research related to the etiology, outcomes, and prevention of brain tumors. The 18th annual BTEC meeting was held in Banff, AB, Canada, on June 27 - 29, 2017. The meeting focused on the intersection between epidemiology and precision medicine, that is, the use of molecular indicators of risk, early disease and prognosis or precision epidemiology. While traditional epidemiologic approaches group large numbers of participants for statistical power, precision epidemiology is founded on the uniqueness and biology of individual disease characteristics. With this in mind, plenary speakers described the molecular heterogeneity of adult and pediatric brain tumors and how those characteristics are currently being used to guide therapy and etiologic research. Rare subtypes and novel mechanisms for recruitment of individuals for research on brain tumors were discussed along with concepts and methodology related to biological and etiologic heterogeneity. The incorporation of relevant molecular classifiers into population registries was emphasized for its role in future research endeavors, ensuring the accessibility of such tools for researchers and clinicians seeking to improve the lives of individuals with brain tumors and those at risk. The next BTEC meeting will be held in Copenhagen, Denmark, in June 2018.
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Association between prediagnostic glucose, triglycerides, cholesterol and meningioma, and reverse causality.

BACKGROUND: Although meningioma is a benign tumour, it may cause significant morbidity. Obesity and diabetes are positively associated with meningioma. To evaluate the potential effects of obesity-related prediagnostic glucose, triglycerides and cholesterol on meningioma and of prediagnostic meningioma on these biomarkers, we conducted a cohort study. METHODS: We identified 41 355 individuals in the Apolipoprotein MOrtality RISk cohort with values for these biomarkers within 15 years before meningioma diagnosis, death, migration or the end of follow-up. We then estimated hazard ratios (HRs) and their interactions with time and age using Cox regression. RESULTS: Meningioma was diagnosed in 181 women and 115 men whose median follow-up time was 7 years. Fasting serum glucose level was inversely related to meningioma among women (Ptrend=0.0006) but not men (Ptrend=0.24). Prediagnostic diabetes was inversely related to meningioma in both sexes combined (HR=0.45, 95% confidence interval (CI) 0.29-0.71), as was serum cholesterol within the year before diagnosis (HR=0.50, 95% CI 0.34-0.72). CONCLUSIONS: Paradoxically, hyperglycaemia is inversely associated with meningioma in women. This finding does not necessarily negate the positive role of obesity or diabetes in meningioma development; rather, it may indicate that their effects depend on the stage of development. Furthermore, the prediagnostic tumour may reduce serum cholesterol levels.

Association Between Prediagnostic Serum 25-Hydroxyvitamin D Concentration and Glioma.

There are no previous studies of the association between prediagnostic serum vitamin D concentration and glioma. Vitamin D has immunosuppressive properties; as does glioma. It was, therefore, our hypothesis that elevated vitamin D concentration would increase glioma risk. We conducted a nested case-control study using specimens from the Janus Serum Bank cohort in Norway. Blood donors who were subsequently diagnosed with glioma (n = 592), between 1974 and 2007, were matched to donors without glioma (n = 1112) on date and age at blood collection and sex. We measured 25-hydroxyvitamin D [25(OH)D], an indicator of vitamin D availability, using liquid chromatography coupled with mass spectrometry. Seasonally adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for each control quintile of 25(OH)D using conditional logistic regression. Among men diagnosed with high grade glioma >56, we found a negative trend (P = .04). Men diagnosed ≤ 56 showed a borderline positive trend (P = .08). High levels (>66 nmol/L) of 25(OH)D in men >56 were inversely related to high grade glioma from ≥2 yr before diagnosis (OR = 0.59; 95% CI = 0.38, 0.91) to ≥15 yr before diagnosis (OR = 0.61; 95% CI = 0.38,0.96). Our findings are consistent long before glioma diagnosis and are therefore unlikely to reflect preclinical disease.

A mathematical model of pre-diagnostic glioma growth.

Due to their location, the malignant gliomas of the brain in humans are very difficult to treat in advanced stages. Blood-based biomarkers for glioma are needed for more accurate evaluation of treatment response as well as early diagnosis. However, biomarker research in primary brain tumors is challenging given their relative rarity and genetic diversity. It is further complicated by variations in the permeability of the blood brain barrier that affects the amount of marker released into the bloodstream. Inspired by recent temporal data indicating a possible decrease in serum glucose levels in patients with gliomas yet to be diagnosed, we present an ordinary differential equation model to capture early stage glioma growth. The model contains glioma-glucose-immune interactions and poses a potential mechanism by which this glucose drop can be explained. We present numerical simulations, parameter sensitivity analysis, linear stability analysis and a numerical experiment whereby we show how a dormant glioma can become malignant.

Loud noise exposure and acoustic neuroma.

The results from studies of loud noise exposure and acoustic neuroma are conflicting. A population-based case-control study of 451 acoustic neuroma patients and 710 age-, sex-, and region-matched controls was conducted in Sweden between 2002 and 2007. Occupational exposure was based on historical measurements of occupational noise (321 job titles summarized by a job exposure matrix) and compared with self-reported occupational noise exposure. We also evaluated self-reported noise exposure during leisure activity. Conditional logistic regression was used to estimate odds ratios. There was no statistically significant association between acoustic neuroma and persistent occupational noise exposure, either with or without hearing protection. Exposure to loud noise from leisure activity without hearing protection was more common among acoustic neuroma cases (odds ratio = 1.47, 95% confidence interval: 1.06, 2.03). Statistically significant odds ratios were found for specific leisure activities including attending concerts/clubs/sporting events (odds ratio = 1.82, 95% confidence interval: 1.09, 3.04) and participating in workouts accompanied by loud music (odds ratio = 2.84, 95% confidence interval: 1.37, 5.89). Our findings do not support an association between occupational exposure to loud noise and acoustic neuroma. Although we report statistically significant associations between leisure-time exposures to loud noise without hearing protection and acoustic neuroma, especially among women, we cannot rule out recall bias as an alternative explanation.

Comorbid conditions associated with glioblastoma.

To inform clinical management of glioblastoma patients, we estimated the relative prevalence (present at glioblastoma diagnosis) and incidence (newly diagnosed) of comorbid conditions among these patients and their matched controls. We identified 2,424 glioblastoma patients registered in the Swedish National Cancer Registry between 1993 and 2006. Next, 12,120 randomly sampled population-based controls were individually matched to cases on age, sex and calendar year of diagnosis. We then evaluated patient discharge data for selected potential comorbid conditions. Seizures (odds ratio (OR) 31.6, 95% confidence interval (CI) 24.7-40.3) and cerebral edema (OR 25.0, 95% CI 5.5-114) were the most prevalent conditions at diagnosis. Beginning 30 days after diagnosis, increased risks of incident deep vein thrombosis (hazard ratio (HR) 119.7, 95% CI 60.8-211.0) and pulmonary embolism (HR 92.4, 95% CI 48.3-176.6) were observed. Risks of incident cardiovascular diseases including heart failure (HR 4.0, 95% CI 2.6-6.1), coronary artery disease (HR 2.3, 95% CI 1.7-3.2), and myocardial infarction (HR 1.9, 95% CI 1.1-3.4) were also elevated among glioblastoma patients. In this first population-based study of both prevalent and incident comorbid conditions among glioblastoma patients, we have quantified risk of those conditions related to the tumor and its treatment-based on nationwide registry data. However, for incident conditions we cannot distinguish between the effects of the tumor and the effects of treatment. A novel finding was the elevated risk of cardiovascular disease among glioblastoma patients; glioblastoma patients should be monitored for signs of cardiovascular disease.

Role of tobacco use in the etiology of acoustic neuroma.

Two previous studies suggest that cigarette smoking reduces acoustic neuroma risk; however, an association between use of snuff tobacco and acoustic neuroma has not been investigated previously. The authors conducted a case-control study in Sweden from 2002 to 2007, in which 451 cases and 710 population-based controls completed questionnaires. Cases and controls were matched on gender, region, and age within 5 years. The authors estimated odds ratios using conditional logistic regression analyses, adjusted for education and tobacco use (snuff use in the smoking analysis and smoking in the snuff analysis). The risk of acoustic neuroma was greatly reduced in male current smokers (odds ratio (OR) = 0.41, 95% confidence interval (CI): 0.23, 0.74) and moderately reduced in female current smokers (OR = 0.70, 95% CI: 0.40, 1.23). In contrast, current snuff use among males was not associated with risk of acoustic neuroma (OR = 0.94, 95% CI: 0.57, 1.55). The authors' findings are consistent with previous reports of lower acoustic neuroma risk among current cigarette smokers than among never smokers. The absence of an association between snuff use and acoustic neuroma suggests that some constituent of tobacco smoke other than nicotine may confer protection against acoustic neuroma.

Attitudes Toward Euthanasia: A Longitudinal Analysis of the Role of Economic, Cultural, and Health-Related Factors.

CONTEXT: It is crucial that physicians understand differing attitudes toward euthanasia and which factors to consider when discussing end-of-life decisions with patients and families from diverse backgrounds. OBJECTIVES: To investigate how attitudes toward euthanasia differ among countries, how they change, and how economic, religious, and health-related factors affect these attitudes. METHODS: We analyzed attitudes toward euthanasia and economic, religious, and health-related indicators using longitudinal (1981-2018) World Values Survey (WVS) data. They included 62 countries with at least a 15-year, three-wave, time series (total n = 389,243 participants). Each national survey interviewed representative samples of adults (mean = 1405). RESULTS: In the latest wave, The Netherlands had the most favorable views of euthanasia (10-point scale with 1 = least justifiable: mean = 7.47) and Jordan the least (mean = 1.50). Residents of 23 of 24 high-income countries came to view euthanasia as more justifiable, while residents of 12 of 38 middle- and low-income countries came to view it as less justifiable over time. The higher GDP per-capita at the time of survey, the more euthanasia was accepted (r = 0.703; P< 0.0001); the more important respondents viewed religion as being, the less euthanasia was accepted (r = -0.834; P< 0.0001); the higher life expectancy and the lower infant mortality were, the more euthanasia was accepted (r = 0.669; P< 0.0001/r = -0.716; P< 0.0001). CONCLUSION: Euthanasia-related attitudes differ widely depending on the cultural context; changes over time varied in both directions; euthanasia-related attitudes were associated with economic, religious and health-related factors. With globalization increasing cultural diversity, these findings can inform physicians' communication about end-of-life decisions with patients and families from diverse backgrounds.

Inherited variation in immune genes and pathways and glioblastoma risk.

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻5 to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.

Bacterial 16S sequence analysis of severe caries in young permanent teeth.

Previous studies have confirmed the association of the acid producers Streptococcus mutans and Lactobacillus spp. with childhood caries, but they also suggested these microorganisms are not sufficient to explain all cases of caries. In addition, health-associated bacterial community profiles are not well understood, including the importance of base production and acid catabolism in pH homeostasis. The bacterial community composition in health and in severe caries of the young permanent dentition was compared using Sanger sequencing of the ribosomal 16S rRNA genes. Lactobacillus species were dominant in severe caries, and levels rose significantly as caries progressed from initial to deep lesions. S. mutans was often observed at high levels in the early stages of caries but also in some healthy subjects and was not statistically significantly associated with caries progression in the overall model. Lactobacillus or S. mutans was found either at low levels or not present in several samples. Other potential acid producers observed at high levels in these subjects included strains of Selenomonas, Neisseria, and Streptococcus mitis. Propionibacterium FMA5 was significantly associated with caries progression but was not found at high levels. An overall loss of community diversity occurred as caries progressed, and species that significantly decreased included the Streptococcus mitis-S. pneumoniae-S. infantis group, Corynebacterium matruchotii, Streptococcus gordonii, Streptococcus cristatus, Capnocytophaga gingivalis, Eubacterium IR009, Campylobacter rectus, and Lachnospiraceae sp. C1. The relationship of acid-base metabolism to 16S rRNA gene-based species assignments appears to be complex, and metagenomic approaches that would allow functional profiling of entire genomes will be helpful in elucidating the microbial pathogenesis of caries.

A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk.

Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.

Occupational exposures and risk of acoustic neuroma.

OBJECTIVES: Acoustic neuroma is a benign tumour accounting for approximately 6-10% of all intracranial tumours and occurs mainly in patients aged ≥50 years. Our aim was to investigate a wide range of occupational exposures, individual occupational titles and socioeconomic status (SES) as potential risk factors for acoustic neuroma. METHODS: We conducted a population-based case-control study of 793 acoustic neuroma cases identified through the Swedish Cancer Registry and 101,762 randomly selected controls. Information on SES and occupation was obtained from censuses and linked to job-exposure matrices. Logistic regression was used to estimate ORs and calculate 95% CIs. RESULTS: An increased OR was seen for mercury exposure <10 years before the reference year (OR 2.9; 95% CI 1.2 to 6.8), and a more modest association for benzene exposure (OR 1.8; 95% CI: 1.0 to 3.2) ≥10 years before the reference year. We observed a threefold increased risk for females working as tailors and dressmakers ≥10 years before the reference year, and a more than threefold significantly elevated OR for those working as truck and conveyor operators <10 years before the reference year. We found no convincing evidence that SES is related to disease development. CONCLUSION: We observed an increased risk of acoustic neuroma associated with occupational exposure to mercury, benzene and textile dust. Men working as truck and conveyor operators <10 years before the reference year had the highest increased risk of acoustic neuroma, but it is unclear what in those occupations might contribute to disease development. Our study also suggested an association between acoustic neuroma and being a class teacher or policeman. However, these findings should be further investigated to exclude the possibility of detection bias.

IgE, allergy, and risk of glioma: update from the San Francisco Bay Area Adult Glioma Study in the temozolomide era.

The consistently observed inverse relationship of allergic conditions with glioma risk and our previous demonstration that immunoglobulin E (IgE) levels also were lower in glioma patients than controls suggest that atopic allergy may be related to a mechanism that inhibits or prevents glioma. We sought to extend these results with a new and larger series of patients (n = 535 with questionnaire data; 393 with IgE measures) and controls (n = 532 with questionnaire data; 470 with IgE measures). As expected, glioma cases were less likely than controls to report history of allergies [among self-reported cases, Odds ratios (OR) = 0.59, 95% confidence interval (CI): 0.41-0.85]. IgE levels also were lower in glioma cases versus controls (OR per unit log IgE = 0.89, 95% CI (0.82-0.98). However, this inverse relationship was only apparent among cases receiving temozolomide, a treatment which became part of the "standard of care" for glioblastoma patients during the study period. Among patients receiving temozolomide, IgE levels in cases whose blood samples were obtained within 30 days of diagnosis were slightly higher than controls, whereas IgE levels in cases whose blood sample was obtained >60 days after diagnosis were significantly lower than controls (OR = 0.80; 95% CI: 0.71-0.89). Thus, although our results robustly confirm the inverse association between allergy and glioma, the results for IgE are affected by temozolomide treatments which may have influenced IgE levels. These results have implications for the study of immunologic factors in glioma as well as for immunotherapy protocols for treating glioma.

Anaerobic muscle strengthening physical activity and depression severity among USA adults.

We investigated the association between depression and anaerobic physical activity (while controlling aerobic physical activity), using a nationally representative sample of USA adults (n = 7354) who participated in the cross sectional National Health and Nutrition Examination Survey (NHANES, 1999-2006). We defined depression using the validated "Patient Health Questionnaire" (PHQ9) scale of 0-27 as PHQ9 ≥ 10. Severity of depression was classified by clinically established PHQ9 levels: mild (5-9), dysthymic (10-14), moderate (15-19), and major depression (≥20). We used logistic regression to estimate adjusted odds ratios of depression associated with distinct types of activity (only aerobic, only anaerobic, combined regime). We used multinomial logistic regression to examine associations of anaerobic activity with various severity levels of depression (mild, dysthymic, moderate, and major depression) with adjustment for aerobic activity. Women had higher prevalence of depression than men (8.4% versus 5.7%), whereas anaerobic muscle strengthening activity was more common in men than women (35% versus 24%). Adjusting for aerobic activity, anaerobic activity was inversely associated with depression (PHQ9 ≥ 10) in women under 50 (OR = 0.57; 95%CI = 0.41-0.81), all women (OR = 0.59; 0.43-0.80), men under 50 (OR = 0.85; 0.58-1.2), and all men (OR = 0.72; 0.51-1.01). Anaerobic activity was inversely associated with severity level of depressive symptoms in women and men. The combined regimen of anaerobic muscle strengthening activity and meeting the Physical Activity Guideline for America (PAGA) was related to the lowest odds ratio of depression in women (OR = 0.50; 95%CI = 0.33-0.75) and men (OR = 0.39; 95%CI = 0.23-0.62). Independent of aerobic physical activity, anaerobic muscle strengthening activity is significantly and inversely associated with depression among USA adults.

Occupational noise exposure and risk of acoustic neuroma.

A small number of prior epidemiologic studies of occupational noise exposure based on self-report have suggested an association with acoustic neuroma. The goal of the present study was to further examine the association between noise exposure and acoustic neuroma by using an objective measure of exposure in the form of a job exposure matrix. A total of 793 acoustic neuroma cases aged 21-84 years were identified between 1987 and 1999 from the Swedish Cancer Registry. The 101,756 controls randomly selected from the study base were frequency matched to cases on age, sex, and calendar year of diagnosis. Occupational information, available for 599 of the cases and 73,432 of the controls, was obtained from censuses and was linked to a job exposure matrix based on actual noise measurements. All risk estimates were close to unity, regardless of noise exposure level or parameter. The overall odds ratio for exposure to > or = 85 dB of noise was 0.89 (95% confidence interval: 0.64, 1.23). Contrary to previous study results, the present findings did not demonstrate an increased acoustic neuroma risk related to occupational noise exposure even after allowing for a long latency period. The effect of nondifferential misclassification of exposure must be considered a potential cause of the negative findings.

An international case-control study of interleukin-4Ralpha, interleukin-13, and cyclooxygenase-2 polymorphisms and glioblastoma risk.

Previous studies found that allergies are inversely related to risk of glioma. In an earlier publication, using data from a Swedish case-control study, Schwartzbaum et al. report an inverse relation between risk of glioblastoma and four single nucleotide polymorphisms (SNP) on two genes [interleukin (IL)-4Ralpha, IL-13] that are associated with allergies. In addition, recent studies suggest that IL-4 and IL-13 induce cyclooxygenase-2 (COX-2) to resolve brain inflammation. To see whether previous Swedish results (110 cases, 430 controls) would be replicated, we estimated the association between glioblastoma and two IL-4Ralpha (rs1805015, rs1801275) and two IL-13 (rs20541, rs1800925) SNPs and their haplotypes and one COX-2 SNP (-765GC) using additional English, Danish, and Finnish data (217 cases, 1,171 controls). Among general population controls, we evaluated associations between these haplotypes, the COX-2 SNP, and self-reported allergies. Our data did not support our original observations relating individual IL-4Ralpha, IL-13, or COX-2 SNPs to glioblastoma risk. However, the T-G IL-4Ralpha haplotype was associated with glioblastoma risk (odds ratio, 2.26; 95% confidence interval, 1.13-4.52) and there was a suggestion of an inverse relation between this haplotype and hayfever prevalence among controls (odds ratio, 0.38; 95% confidence interval, 0.14-1.03). The lack of support for a link between four IL-4Ralpha and IL-13 SNPs and glioblastoma may reflect the absence of associations or may result from uncontrolled confounding by haplotypes related both to those that we examined and glioblastoma. Nonetheless, the association between the T-G IL-4Ralpha haplotype and glioblastoma risk may indicate a role of immune factors in glioblastoma development.