| 1. |
- Berntsson, Shala G., 1964-, et al.
(författare)
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Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study.
- 2018
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Ingår i: Journal of neurology. - : Springer Science and Business Media LLC. - 1432-1459 .- 0340-5354. ; 265:6, s. 1432-1442
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls.The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n=4533) and controls (n=4171) were also asked about seizures less than 2years from diagnosis and previous seizure history more than 2years prior to tumor diagnosis, including childhood seizures.Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p<0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood.Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma.
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| 2. |
- Disney-Hogg, Linden, et al.
(författare)
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Impact of atopy on risk of glioma : a Mendelian randomisation study
- 2018
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Ingår i: BMC Medicine. - : BioMed Central. - 1741-7015. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.Methods: Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis.Results: Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194).Conclusions: Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.
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| 3. |
- Disney-Hogg, Linden, et al.
(författare)
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Influence of obesity-related risk factors in the aetiology of glioma
- 2018
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Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 118:7, s. 1020-1027
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship. RESULTS: No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non-GBM tumours. CONCLUSIONS: This study provides no evidence to implicate obesity-related factors as causes of glioma.
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| 4. |
- Eckel-Passow, Jeanette, et al.
(författare)
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USING GERMLINE VARIANTS TO PREDICT GLIOMA RISK AND IDENTIFY GLIOMA SUBTYPE PRE-OPERATIVELY
- 2018
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Ingår i: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 20, s. 82-82
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- To date, 25 single nucleotide polymorphisms (SNPs) have been shown to be associated with overall glioma risk or with risk of specific subtypes of glioma. We hypothesized that the inclusion of these 25 SNPs with patient age at diagnosis and sex could predict risk of glioma as well as predict IDH mutation status. Thus, case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for molecular subtypes. Case-case design and logistic regression were used to develop models to predict IDH mutation status. Each model included all 25 glioma risk SNPs, patient age at diagnosis and sex. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray. We observed that patients in the highest 5% of the risk score had more than a 14-fold increased relative risk of developing an IDH-mutant glioma, compared to patients with median risk score. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile categories. For both IDH-mutated 1p/19q non-codeleted glioma and IDH-mutated 1p/19q-codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation c-index of 0.85. These results suggest that germline genotyping has the potential to provide a new tool for clinicians for the initial management of newly-discovered brain lesions. Specifically, given the low lifetime risk of glioma, SNP-based risk scores should not be useful for general population screening. However, with further research these risk scores may be useful in certain clinically-defined high-risk groups.
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| 5. |
- Jacobs, Daniel I., et al.
(författare)
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Elucidating the molecular pathogenesis of familial glioma
- 2018
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, the molecular characterization of sporadically arising diffuse gliomas has identified recurrent driving alterations and delineated molecularly and clinically distinct subclasses of disease. However, less is known about the molecular nature of gliomas that are familial in origin. To address this question, we integrated germline and somatic genomic data to characterize the molecular pathogenesis of 20 tumors arising in unrelated individuals with a family history of glioma collected through the Gliogene International Consortium. METHODS: FFPE tumor specimens were sectioned and reviewed to localize neoplastic tissue for DNA extraction. Library preparation, exome plus targeted capture, and paired-end sequencing on the Illumina HiSeq 2000 platform was performed at the Baylor College of Medicine Human Genome Sequencing Center. Single-nucleotide variants and indels were called with respect to germline DNA sequencing data for each case using MuTect2. Copy number profiling was performed on the Illumina HumanOmniExpress BeadChip and analyzed using GenomeStudio v2.0. Genotypes at known glioma risk polymorphisms were determined from germline DNA profiled on the Illumina Infinium OncoArray and rare, predicted deleterious germline mutations were identified from germline whole-exome sequencing data. RESULTS: Tumor exome sequencing was completed at an average read depth of 116X and we detected a median of 54 non-silent somatic mutations per tumor across the 20 tumors profiled. All three molecular subtypes of sporadic glioma were represented, including IDH-mutant, 1p/19q codeleted (n=3), IDH-mutant, 1p/19q intact (n=7), and IDH-wildtype tumors (n=10). Characteristic subtype-specific mutations and copy number alterations (e.g., TP53 and ATRX mutations among IDH-mutant, 1p/19q intact tumors) were observed, and the frequencies of recurrent alterations were comparable to sporadic glioma cases analyzed by The Cancer Genome Atlas. Notably, all 20 cases had alterations in genes regulating telomere length; 17 had acquired mutations in ATRX or the TERT promoter as typically seen in sporadic glioma, while three instead had germline mutations in telomere shelterin complex genes POT1 or TERF2. Frequencies of known common glioma risk alleles were similar to those among sporadic cases and correlations between risk alleles and specific somatic mutations were not observed. CONCLUSIONS: This study illustrates: 1) the complementarity of inherited and acquired alterations in driving gliomagenesis in some individuals with a familial predisposition to the disease; and 2) that the molecular characteristics of familial tumors profiled largely recapitulate what is known about sporadic glioma. In the majority of cases, the source of germline genetic susceptibility is not known but does not appear to be conferred by common risk polymorphisms.
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| 6. |
- Ostrom, Quinn, et al.
(författare)
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PREVIOUSLY IDENTIFIED COMMON GLIOMA RISK SNPs ARE ASSOCIATED WITH FAMILIAL GLIOMA
- 2018
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Ingår i: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 20, s. 108-108
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Approximately 5% of gliomas occur in individuals with a family history of glioma, and first-degree relatives of brain tumor cases have a two-fold increase in risk of brain tumor. Family-based studies have had little success in identifying high penetrance risk variants. Recent somatic characterization has shown that tumors from familial cases are indistinguishable from sporadic cases, suggesting that familial cases may arise through similar mechanisms of gliomagenesis, and therefore may be associated with common variants as well as rare mutations. In this analysis, we assessed whether previously identified common risk variants are associated with familial glioma. METHODS: Data were obtained from the Glioma International Case Control (GICC) Study for 447 familial cases and 3,286 controls. We assessed 25 risk loci previously identified by glioma GWAS, and odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using an additive genetic logistic regression model adjusted for age, sex, and the first principal component. Results were considered significant at p TERT, EGFR, CCDC26, CDKN2B, TP53, and RTEL1. The strongest association was at rs55705857 (CCDC26, OR=2.5, p=1.14x10-14). These SNPs were further examined using a caseonly approach comparing familial to non-familial cases, and there was no significant difference in allele frequencies by family history status. CONCLUSIONS: In this analysis we identified a significant association between familial glioma and six common risk variants previously identified by glioma GWAS. This provides further evidence of shared pathways of genetic risk and gliomagenesis between familial and non-familial glioma. Further exploration is necessary to determine the overall contribution of common genetic variation to risk of familial glioma.
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| 7. |
- Ostrom, Quinn T., et al.
(författare)
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Age‐specific genome‐wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'‐like features associated with younger age
- 2018
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Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 143:10, s. 2359-2366
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Tidskriftsartikel (refereegranskat)abstract
- 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.’
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| 8. |
- Ostrom, Quinn T., et al.
(författare)
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Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos
- 2018
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only, and it is unknown whether variants identified by these analyses are associated with glioma in non- European ancestry populations. African Americans and Hispanics are admixed populations with varying proportions of European ancestry. While global ancestry may be similar within admixed groups, the proportion of European ancestry at each allele can vary across the genome. As glioma is more common in European ancestry populations, the presence of increased local European ancestry in these admixed populations could be used to identify glioma risk loci. Here we assessed whether excess European ancestry at established risk loci (Melin et al, Nature Genetics, 2017) was associated with glioma risk in non-European ancestry populations. Global ancestry was estimated using fastStructure, and local ancestry was estimated using RFMix. Both methods used 1,000 genomes project reference populations (African: YRI; European: CEU; East Asian: CHB/JPT; and Native American: CLM/PEL/MXL). We evaluated differences in local European ancestry between cases and controls using logistic regression conditioned on global European ancestry within 500kb of 25 previously identified risk variants among individuals with ≥50% African ancestry, and ≥30% Native American ancestry for all gliomas, and for grade IV glioblastoma (GBM) and grade II-III non-GBM. There were 347 individuals (184 cases and 163 controls) with ≥50% global African ancestry, and 277 individuals (153 cases and 124 controls) with ≥30% global American ancestry. There was no significant difference in proportion of global European ancestry between cases and controls with ≥50% global African ancestry (cases: 18.2%, controls: 17.7%, p=0.6834), and no significant difference in proportion of global European ancestry between cases and controls with ≥30% global American ancestry (cases: 51.1%, controls: 49.0%, p=0.2123). Among individuals with >50% African ancestry, we observed a nominally significant association between all glioma and increased local European ancestry at 7p11.2 (EGFR, pmin=0.0070) and between GBM and increased local European ancestry at 22q13.1 (CSNK1E, pmin=0.0098), both near SNPs previously associated with glioblastoma in majority European-ancestry populations. The dataset used for this analysis represents the largest collection of genotyped non-European glioma cases. These results suggest that glioma risk in African Americans may be associated with an increased local European ancestry variants at glioma risk loci previously identified in majority European ancestry populations (7p11.2 and 22q13.1).
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| 9. |
- Ostrom, Quinn T., et al.
(författare)
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Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Ruiz, Vanessa Y., et al.
(författare)
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Molecular subtyping of tumors from patients with familial glioma
- 2018
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 20:6, s. 810-817
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Tidskriftsartikel (refereegranskat)abstract
- Background. Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas and that tumors in the same family should have the same molecular subtype. Methods. Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded tumors were obtained from a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation data were obtained using a first-generation Affymetrix molecular inversion probe (MIP) array. Results. Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wildtype, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (P = 0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (kappa = 0.59): 3 IDH-mutant non-codeleted, 2 IDH-wildtype, and 2 IDH-mutant and 1p/19q codeleted gliomas. Conclusions. Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight into the distribution of molecular subtypes in FG.
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