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BackgroundThe Brain Tumor Social Media (#BTSM) Twitter hashtag was founded in February 2012 as a disease-specific hashtag for patients with brain tumor. ObjectiveTo understand #BTSM’s role as a patient support system, we describe user descriptors, growth, interaction, and content sharing. MethodsWe analyzed all tweets containing #BTSM from 2012 to 2018 using the Symplur Signals platform to obtain data and to describe Symplur-defined user categories, tweet content, and trends in use over time. We created a network plot with all publicly available retweets involving #BTSM in 2018 to visualize key stakeholders and their connections to other users. ResultsFrom 2012 to 2018, 59,764 unique users participated in #BTSM, amassing 298,904 tweets. The yearly volume of #BTSM tweets increased by 264.57% from 16,394 in 2012 to 43,373 in 2018 with #BTSM constantly trending in the top 15 list of disease hashtags, as well the top 15 list of tweet chats. Patient advocates generated the most #BTSM tweets (33.13%), while advocacy groups, caregivers, doctors, and researchers generated 7.01%, 4.63%, 3.86%, and 3.37%, respectively. Physician use, although still low, has increased over time. The 2018 network plot of retweets including #BTSM identifies a number of key stakeholders from the patient advocate, patient organization, and medical researcher domains and reveals the extent of their reach to other users. ConclusionsFrom its start in 2012, #BTSM has grown exponentially over time. We believe its growth suggests its potential as a global source of brain tumor information on Twitter for patients, advocates, patient organizations as well as health care professionals and researchers.

BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

PurposeTelomere length-associated SNPs have been associated with incidence and survival rates for malignant brain tumors such as glioma. Here, we study the influence of genetically determined lymphocyte telomere length (LTL) by comparing telomerase associated SNPs between the most common non-malignant brain tumor, i.e. meningioma, and healthy controls.Methods/patientsOne thousand fifty-three (1053) surgically treated meningioma patients and 4437 controls of Western European ancestry were included. Germline DNA was genotyped for 8 SNPs previously significantly associated with LTL. Genotypically-estimated LTL was then calculated by summing each SNP's genotypically-specified telomere length increase in base pairs (bp) for each person. Odds ratios for genotypically-estimated LTL in meningioma cases and controls were evaluated using logistic regression with the first two ancestral principal components and sex as covariates.ResultsThree out of the eight evaluated LTL SNPs were significantly associated with increased meningioma risk (rs10936599: OR 1.14, 95% CI 1.01-1.28, rs2736100: OR 1.13, 95% CI 1.03-1.25, rs9420907: OR 1.22, 95% CI 1.07-1.39). Only rs9420907 remained significant after correction for multiple testing. Average genotypically-estimated LTL was significantly longer for those with meningioma compared to controls [mean cases: 560.2 bp (standard error (SE): 4.05 bp), mean controls: 541.5 bp (SE: 2.02 bp), logistic regression p value = 2.13 × 10-5].ConclusionIncreased genotypically-estimated LTL was significantly associated with increased meningioma risk. A role for telomere length in the pathophysiology of meningioma is novel, and could lead to new insights on the etiology of meningioma.

Little is known about the causes of meningioma. Obesity and obesity-related traits have been reported in several epidemiological observational studies to be risk factors for meningioma. We performed an analysis of genetic variants associated with obesity-related traits to assess the relationship with meningioma risk using Mendelian randomization (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. We considered 11 obesity-related traits, identified genetic instruments for these factors, and assessed their association with meningioma risk using data from a genome-wide association study comprising 1,606 meningioma patients and 9,823 controls. To evaluate the causal relationship between the obesity-related traits and meningioma risk, we consider the estimated odds ratio (OR) of meningioma for each genetic instrument. We identified positive associations between body mass index (odds ratio [ORSD] = 1.27, 95% confidence interval [CI] = 1.03-1.56, P = 0.028) and body fat percentage (ORSD = 1.28, 95% CI = 1.01-1.63, P = 0.042) with meningioma risk, albeit non-significant after correction for multiple testing. Associations for basal metabolic rate, diastolic blood pressure, fasting glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, total cholesterol, triglycerides and waist circumference with risk of meningioma were non-significant. Our analysis provides additional support for obesity being associated with an increased risk of meningioma.

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54-63 = 1.50x10-9 , OR54-63 = 1.28, 95%CI54-63 = 1.18-1.39; p64+ = 2.14x10-11 , OR64+ = 1.32, 95%CI64+ = 1.21-1.43] and rs11979158 [p54-63 = 6.13x10-8 , OR54-63 = 1.35, 95%CI54-63 = 1.21-1.50; p64+ = 2.18x10-10 , OR64+ = 1.42, 95%CI64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p18-53 = 9.30 × 10-11 , OR18-53 = 1.76, 95%CI18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'

BackgroundMeningiomas are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome-wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31.MethodsTo identify a susceptibility locus for meningioma, we conducted a meta-analysis of 2 GWAS, imputed using a merged reference panel from the 1000 Genomes Project and UK10K data, with validation in 2 independent sample series totaling 2138 cases and 12081 controls.ResultsWe identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 × 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges.ConclusionsThis finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma.

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities and, ultimately, improved outcomes for a patient population in need.

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

To examine for a causal relationship between vitamin D and glioma risk we performed an analysis of genetic variants associated with serum 25-hydroxyvitamin D (25(OH)D) levels using Mendelian randomisation (MR), an approach unaffected by biases from confounding. Two-sample MR was undertaken using genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D levels were used as instrumental variables (IVs). We calculated MR estimates for the odds ratio (OR) for 25(OH)D levels with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighted (IVW) and maximum likelihood estimation (MLE) methods. A non-significant association between 25(OH)D levels and glioma risk was shown using both the IVW (OR = 1.21, 95% confidence interval [CI] = 0.90-1.62, P = 0.201) and MLE (OR = 1.20, 95% CI = 0.98-1.48, P = 0.083) methods. In an exploratory analysis of tumour subtype, an inverse relationship between 25(OH)D levels and glioblastoma (GBM) risk was identified using the MLE method (OR = 0.62, 95% CI = 0.43-0.89, P = 0.010), but not the IVW method (OR = 0.62, 95% CI = 0.37-1.04, P = 0.070). No statistically significant association was shown between 25(OH)D levels and non-GBM glioma. Our results do not provide evidence for a causal relationship between 25(OH)D levels and all forms of glioma risk. More evidence is required to explore the relationship between 25(OH)D levels and risk of GBM.

BackgroundTo the authors' knowledge, limited data exist regarding long-term quality of life (QOL) for patients diagnosed with intracranial meningioma.MethodsThe data in the current study concerned 1722 meningioma cases diagnosed among residents of Connecticut, Massachusetts, California, Texas, and North Carolina from May 1, 2006 through March 14, 2013, and 1622 controls who were frequency matched to the cases by age, sex, and geography. These individuals were participants in a large, population-based, case-control study. Telephone interviews were used to collect data regarding QOL at the time of initial diagnosis or contact, using the Medical Outcomes Study Short-Form 36 Health Survey. QOL outcomes were compared by case/control status.ResultsPatients diagnosed with meningioma reported levels of physical, emotional, and mental health functioning below those reported in a general healthy population. Case participants and controls differed most significantly with regard to the domains of Physical and Social Functioning, Role-Physical, Role-Emotional, and Vitality.ConclusionsIn the current study, patients with meningioma experienced statistically significant decreases in QOL compared with healthy controls of a similar demographic breakdown, although these differences were found to vary in clinical significance. Cancer 2018;124:161-6. © 2017 American Cancer Society.

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.

Significant gaps exist in our understanding of the causes and clinical management of glioma. One of the biggest gaps is how best to manage low-grade (World Health Organization [WHO] Grade II) glioma. Low-grade glioma (LGG) is a uniformly fatal disease of young adults (mean age 41 years), with survival averaging approximately 7 years. Although LGG patients have better survival than patients with high-grade (WHO Grade III or IV) glioma, all LGGs eventually progress to high-grade glioma and death. Data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute suggest that for the majority of LGG patients, overall survival has not significantly improved over the past 3 decades, highlighting the need for intensified study of this tumor. Recently published research suggests that historically used clinical variables are not sufficient (and are likely inferior) prognostic and predictive indicators relative to information provided by recently discovered tumor markers (e.g., 1p/19q deletion and IDH1 or IDH2 mutation status), tumor expression profiles (e.g., the proneural profile) and/or constitutive genotype (e.g., rs55705857 on 8q24.21). Discovery of such tumor and constitutive variation may identify variables needed to improve randomization in clinical trials as well as identify patients more sensitive to current treatments and targets for improved treatment in the future. This article reports on survival trends for patients diagnosed with LGG within the United States from 1973 through 2011 and reviews the emerging role of tumor and constitutive genetics in refining risk stratification, defining targeted therapy, and improving survival for this group of relatively young patients.

ObjectMeningioma is a disease with considerable morbidity and is more commonly diagnosed in females than in males. Hormonally related risk factors have long been postulated to be associated with meningioma risk, but no examination of these factors has been undertaken in males.MethodsSubjects were male patients with intracranial meningioma (n = 456), ranging in age from 20 to 79 years, who were diagnosed among residents of the states of Connecticut, Massachusetts, and North Carolina, the San Francisco Bay Area, and 8 counties in Texas and matched controls (n = 452). Multivariate logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between hormonal factors and meningioma risk in men.ResultsUse of soy and tofu products was inversely associated with meningioma risk (OR 0.50 [95% CI 0.37-0.68]). Increased body mass index (BMI) appears to be associated with an approximately 2-fold increased risk of developing meningioma in men. No other single hormone-related exposure was found to be associated with meningioma risk, although the prevalence of exposure to factors such as orchiectomy and vasectomy was very low.ConclusionsEstrogen-like exogenous exposures, such as soy and tofu, may be associated with reduced risk of meningioma in men. Endogenous estrogen-associated factors such as high BMI may increase risk. Examination of other exposures related to these factors may lead to better understanding of mechanisms and potentially to intervention.

BackgroundWhile certain inherited syndromes (e.g. Neurofibromatosis or Li-Fraumeni) are associated with an increased risk of glioma, most familial gliomas are non-syndromic. This study describes the demographic and clinical characteristics of the largest series of non-syndromic glioma families ascertained from 14 centres in the United States (US), Europe and Israel as part of the Gliogene Consortium.MethodsFamilies with 2 or more verified gliomas were recruited between January 2007 and February 2011. Distributions of demographic characteristics and clinical variables of gliomas in the families were described based on information derived from personal questionnaires.FindingsThe study population comprised 841 glioma patients identified in 376 families (9797 individuals). There were more cases of glioma among males, with a male to female ratio of 1.25. In most families (83%), 2 gliomas were reported, with 3 and 4 gliomas in 13% and 3% of the families, respectively. For families with 2 gliomas, 57% were among 1st-degree relatives, and 31.5% among 2nd-degree relatives. Overall, the mean (±standard deviation [SD]) diagnosis age was 49.4 (±18.7) years. In 48% of families with 2 gliomas, at least one was diagnosed at

ObjectThe 2-fold higher incidence of meningioma in women compared with men has long suggested a role for hormonally mediated risk factors, but specific mechanisms remain elusive.MethodsThe study included data obtained in 1127 women 29-79 years of age with intracranial meningioma diagnosed among residents of Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area, and 8 Texas counties between May 1, 2006, and October 6, 2011, and data obtained in 1092 control individuals who were frequency matched for age group and geography with meningioma patients.ResultsNo association was observed for age at menarche, age at menopause, or parity and meningioma risk. Women who reported breastfeeding for at least 6 months were at reduced risk of meningioma (OR 0.78, 95% CI 0.63-0.96). A significant positive association existed between meningioma risk and increased body mass index (p < 0.01) while a significant negative association existed between meningioma risk and current smoking (p < 0.01). Among premenopausal women, current use of oral contraceptives was associated with an increased risk of meningiomas (OR 1.8, 95% CI 1.1-2.9), while current use of hormone replacement therapy among postmenopausal women was not associated with a significant elevation in risk (OR 1.1, 95% CI 0.74-1.67). There was no association between use of fertility medications and meningioma risk.ConclusionsThe authors' study confirms associations for body mass index, breastfeeding, and cigarette smoking but provides little evidence for associations of reproductive and menstrual factors with meningioma risk. The relationship between current use of exogenous hormones and meningioma remains unclear, limited by the small numbers of patients currently on oral hormone medications and a lack of hormone receptor data for meningioma tumors.

Report of past dental x-rays has been reported to be associated with the diagnosis of intracranial meningioma. The authors respond to commentary regarding their recent case/control study of the topic.

Meningioma is an intracranial tumor with few confirmed risk factors. Recent research points to an impact on meningioma risk from factors related to immune function and development, such as allergy, immunoglobulin E, and Varicella infection status. To further explore an association with immune function, the authors assessed individual seroreactivity to meningioma tumor-associated antigens among participants enrolled in a multicenter, population-based US case-control study of meningioma (2006-2009). Serum samples from cases (n = 349) and controls (n = 348) were screened for autoantibody reactivity to 3 proteins identified in previous studies: enolase 1 (ENO1), NK-tumor recognition protein (NKTR), and nuclear mitotic apparatus protein 1 (NUMA1). Case-control differences were not strong overall (adjusted odds ratio (OR)(ENO1 (continuous)) = 1.1, 95% confidence interval (CI): 0.6, 1.9 (P(trend) = 0.3); adjusted OR(NKTR (continuous)) = 1.3, 95% CI: 0.7, 2.4 (P(trend) = 0.02); and adjusted OR(NUMA1 (continuous)) = 1.1, 95% CI: 0.7, 1.8 (P(trend) = 0.06)); however, antibodies to NKTR and NUMA1 were detected at higher levels in cases than in controls, particularly among men (for men, adjusted OR(ENO1 (continuous)) = 1.6, 95% CI: 0.5, 4.7 (P(trend) = 0.24); adjusted OR(NKTR (continuous)) = 4.3, 95% CI: 1.2, 15 (P(trend) = 0.009); and adjusted OR(NUMA1 (continuous)) = 3.6, 95% CI: 1.1, 11 (P(trend) = 0.006)). These results indicate that men with meningioma commonly react with a serologic antimeningioma response; if supported by further research, this finding suggests a distinctive etiology for meningioma in men.

The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (P(trend)

BackgroundA number of studies have reported on the association between smoking and meningioma risk, with inconsistent findings. We examined the effect of gender on the association between cigarette smoking and risk of intracranial meningioma in a large population-based, case-control study.MethodsThe data include 1,433 intracranial meningioma cases aged 29 to 79 years diagnosed among residents of the states of Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area and eight Texas counties between May 1, 2006 and April 28, 2011 as well as 1,349 controls that were frequency matched on age, sex, and geography. The data are analyzed separately and in a meta-analysis with six previously reported studies.ResultsFemale cases who reported having ever smoked were at significantly decreased risk of intracranial meningioma (OR, 0.8; 95% CI, 0.7-0.9) in contrast to male cases who were at increased risk (OR, 1.3; 95% CI, 1.0-1.7). Similar findings were noted for current and past smokers. Smoking-induced risk for females did not vary by menopausal status. For males, increased duration of use (P = 0.04) as well as increasing number of pack-years (P = 0.02) was associated with elevated risk. A meta-analysis including 2,614 cases and 1,179,686 controls resulted in an OR for ever smoking of 0.82 (95% CI, 0.68-0.98) for women and 1.39 (95% CI, 1.08-1.79) for men.ConclusionThe association of cigarette smoking and meningioma case status varies significantly by gender with women at reduced risk and men at greater risk.ImpactWhether the observed differences are associated with a hormonal etiology will require additional investigation.

Although most meningiomas are encapsulated and benign tumors with limited numbers of genetic aberrations, their intracranial location often leads to serious and potentially lethal consequences. They are the most frequently diagnosed primary brain tumor accounting for 33.8% of all primary brain and central nervous system tumors reported in the United States between 2002 and 2006. Inherited susceptibility to meningioma is suggested both by family history and candidate gene studies in DNA repair genes. People with certain mutations in the neurofibromatosis gene (NF2) have a very substantial increased risk for meningioma. High dose ionizing radiation exposure is an established risk factor for meningioma, and lower doses may also increase risk, but which types and doses are controversial or understudied. Because women are twice as likely as men to develop meningiomas and these tumors harbor hormone receptors, an etiologic role for hormones (both endogenous and exogenous) has been hypothesized. The extent to which immunologic factors influence meningioma etiology has been largely unexplored. Growing emphasis on brain tumor research coupled with the advent of new genetic and molecular epidemiologic tools in genetic and molecular epidemiology promise hope for advancing knowledge about the causes of intra-cranial meningioma. In this review, we highlight current knowledge about meningioma epidemiology and etiology and suggest future research directions.

Background: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research. Methods: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities in participant engagement: (i) a brainstorming exercise to elicit potential priorities; (ii) a 2-day virtual meeting to discuss priorities; (iii) recommendations from the PE-CGS External Advisory Panel to refine priorities; and (iv) a virtual meeting to set priorities. Results: Nearly 150 PE-CGS stakeholders engaged in the process. Five priorities were set: (i) tailor education and communication materials for participants throughout the research process; (ii) identify measures of participant engagement; (iii) identify optimal participant engagement strategies; (iv) understand cancer disparities in the context of cancer genomics research; and (v) personalize the return of genomics findings to participants. Conclusions: PE-CGS is pursuing these priorities to meaningfully engage diverse and underrepresented patients with cancer and posttreatment cancer survivors as participants in cancer genomics research and, subsequently, generate new discoveries. Impact: Data from PE-CGS will be shared with the broader scientific community in a manner consistent with participant informed consent and community agreement. [ABSTRACT FROM AUTHOR]

Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), ≡and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM., To develop therapeutic strategies for HER2-positive BCBM, we established a panel of orthotopic PDXs (Fig. 1a). Fresh BCBMs from two patients, Dana-Farber Brain Metastasis (DF-BM)354 and DF-BM355, were grafted directly [...]

Background: The functions of most glioma risk alleles are unknown. Very few studies had evaluated expression quantitative trait loci (eQTL), and insights of susceptibility genes were limited due to scarcity of available brain tissues. Moreover, no prior study had examined the effect of glioma risk alleles on alternative RNA splicing. Objective: This study explored splicing quantitative trait loci (sQTL) as molecular QTL and improved the power of QTL mapping through meta-analyses of both cis eQTL and sQTL. Methods: We first evaluated eQTLs and sQTLs of the CommonMind Consortium (CMC) and Genotype-Tissue Expression Project (GTEx) using genotyping, or whole-genome sequencing and RNA-seq data. Alternative splicing events were characterized using an annotation-free method that detected intron excision events. Then, we conducted meta-analyses by pooling the eQTL and sQTL results of CMC and GTEx using the inverse variance-weighted model. Afterward, we integrated QTL meta-analysis results (Q < 0.05) with the Glioma International Case Control Study (GICC) GWAS meta-analysis (case:12,496, control:18,190), using a summary statistics-based mendelian randomization (SMR) method. Results: Between CMC and GTEx, we combined the QTL data of 354 unique individuals of European ancestry. SMR analyses revealed 15 eQTLs in 11 loci and 32 sQTLs in 9 loci relevant to glioma risk. Two loci only harbored sQTLs (1q44 and 16p13.3). In seven loci, both eQTL and sQTL coexisted (2q33.3, 7p11.2, 11q23.3 15q24.2, 16p12.1, 20q13.33, and 22q13.1), but the target genes were different for five of these seven loci. Three eQTL loci (9p21.3, 20q13.33, and 22q13.1) and 4 sQTL loci (11q23.3, 16p13.3, 16q12.1, and 20q13.33) harbored multiple target genes. Eight target genes of sQTLs (C2orf80 , SEC61G , TMEM25 , PHLDB1 , RP11-161M6.2 , HEATR3 , RTEL1-TNFRSF6B , and LIME1) had multiple alternatively spliced transcripts. Conclusion: Our study revealed that the regulation of transcriptome by glioma risk alleles is complex, with the potential for eQTL and sQTL jointly affecting gliomagenesis in risk loci. QTLs of many loci involved multiple target genes, some of which were specific to alternative splicing. Therefore, quantitative trait loci that evaluate only total gene expression will miss many important target genes. [ABSTRACT FROM AUTHOR]