Terri Rice

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors

BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility.

The causes of glioblastoma and other gliomas remain obscure. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component–adjusted genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA)) and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P < 10−6 using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 × 10−8, replication P = 0.0038 and combined P = 1.85 × 10−10. On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 × 10−7, replication P = 0.00035 and combined P = 3.40 × 10−9. For both SNPs, the direction of association was the same in discovery and replication phases.

A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation

Variants at 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR and subsequent validation SNP genotyping, we identified seven low-frequency SNPs at 8q24.21 that were strongly associated with glioma risk (P = 1 × 10−25 to 1 × 10−14). The most strongly associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six SNPs and two previously published SNPs. After stratifying by histological and tumor genetic subtype, the most significant associations of rs55705857 were with oligodendroglial tumors and gliomas with mutant IDH1 or IDH2 (odds ratio (OR) = 5.1, P = 1.1 × 10−31 and OR = 4.8, P = 6.6 × 10−22, respectively). Strong associations were observed for astrocytomas with mutated IDH1 or IDH2 (grades 2–4) (OR = 5.16–6.66, P = 4.7 × 10−12 to 2.2 × 10−8) but not for astrocytomas with wild-type IDH1 and IDH2 (smallest P = 0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.

Diagnostic, treatment, and demographic factors influencing survival in a population-based study of adult glioma patients in the San Francisco Bay Area

We compare survival estimates for population-based glioma cases by using two diagnostic coding schemes, (1) the International Classification of Diseases, Oncology, second edition (ICD-O-2) as reported by the Surveillance, Epidemiology, and End Results (SEER) program and (2) central neuropathology review diagnosis based on the World Health Organization II classification. In addition, among review categories, we estimate survival in relation to several patient demographic and treatment factors. Eligible cases included adults residing in the San Francisco Bay SEER Area with newly diagnosed, histologically confirmed glioma during the years 1991-1994 and 1997-1999. The study group included participating subjects for whom subsequent central neuropathology review confirmed glioma. We determined treatments, vital status, and other factors by using registry, interview, medical record, and active follow-up data. Survival differences between anaplastic astrocytoma (AA) and astrocytoma were apparent from review diagnoses (median months of survival for AA, 13.0 [95% CI, 9.9-19.5], and astrocytoma, 101.3 [95% CI lower limit, 42.1; upper limit not yet reached]), but not with ICD-O-2 diagnoses reported by SEER (median months of survival for AA, 16.6 [95% CI, 12.0-20.7], and astrocytoma, not otherwise specified, 17.2 [95% CI, 10.6-71.6]). This finding emphasizes the need for improvements in coding for nonglioblastoma astrocytomas to provide better population survival estimates. When review diagnosis was used, younger age and resection (vs. biopsy) were statistically significant for all histology groups analyzed by multivariable Cox proportional hazard models. Additional statistically significant variables were as follows: among 517 glioblastoma patients, radiation treatment and being married; among 105 AA patients, inclusion of chemotherapy in the initial treatment; and among 106 patients with nonanaplastic oligodendroglial tumors, college education. Further consideration of impact of marital status, education, and other social factors in glioma survival may be warranted.

Allergy-Related Polymorphisms Influence Glioma Status and Serum IgE Levels

Previous studies have shown that glioma patients report allergies less frequently than controls, harbor lower atopy-associated IgE levels, and harbor different frequencies of polymorphisms in the IL13 and IL4 pathways than controls. We sought to confirm this latter result and extend the analysis to IgE levels. Glioma patients (n = 456) and controls (n = 541) were genotyped for genetic variants in IL4, IL4R, and IL13 and tested for total IgE levels (n = 248 controls and 289 cases). Among Whites, IL4 and IL4R polymorphisms and haplotypes were neither significantly associated with IgE levels in controls nor associated with glioma status. IL13 R110G and C-1112T were associated with increased IgE levels in controls (P < 0.001 and P = 0.04, respectively), and IL13 C-1112T was inversely associated with case-control status (P = 0.05, test for trend in dose model). An IL4R haplotype was borderline associated with increased risk in case-control analysis [odds ratio (OR), 1.5; 95% confidence interval (95% CI), 1.0-2.3]. In addition, a rare haplotype for IL4 was associated with decreased risk (OR, 0.23; 95% CI, 0.07-0.83), and a common haplotype in IL13 was associated with decreased risk (OR, 0.73; 95% CI, 0.53-1.00). Our data provide evidence for a role of IL13 polymorphisms on IgE levels and a role for IL4, IL4R, and IL13 haplotypes on case-control status. We did not find any evidence that the interleukin (IL) polymorphisms exerted their effect on glioma risk via their effects on IgE levels. Further exploration of immune susceptibility factors, including genetics, in glioma etiology is advisable. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1229–35)

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.

DNA Repair Polymorphisms XRCC1 and MGMT and Risk of Adult Gliomas

X-ray cross complementing group 1 (XRCC1) and O6-methylguanine-DNA methyltransferase (MGMT) are pivotal repair genes focused on repairing lesions due to ionizing radiation, alkylating agents, and oxidative DNA damage, risk factors previously linked to gliomas. Using the population based San Francisco Adult Glioma study, we evaluated associations between XRCC1 Arg399Gln, MGMT Leu84Phe, and MGMT Ile143Val polymorphisms with glioma risk among white cases (n = 441 to 453) and controls (n = 487 to 526). We found no evidence of an association between XRCC1 genotypes and glioma. We observed a weak positive association for the MGMT Leu84Phe polymorphism (Leu or Phe/Phe versus Leu/Leu: adjusted OR = 1.26; CI 0.90–1.75) and the MGMT Ile143Val polymorphism (Ile or Val/Val versus Ile/Ile: adjusted OR = 1.20; CI 0.85–1.71).

Pathway Analysis of Single-Nucleotide Polymorphisms Potentially Associated with Glioblastoma Multiforme Susceptibility Using Random Forests

Glioma is a complex disease that is unlikely to result from the effect of a single gene. Genetic analysis at the pathway level involving multiple genes may be more likely to capture gene-disease associations than analyzing genes one at a time. The current pilot study included 112 Caucasians with glioblastoma multiforme and 112 Caucasian healthy controls frequency matched to cases by age and gender. Subjects were genotyped using a commercially available (ParAllele/Affymetrix) assay panel of 10,177 nonsynonymous coding single-nucleotide polymorphisms (SNP) spanning the genome known at the time the panel was constructed. For this analysis, we selected 10 pathways potentially involved in gliomagenesis that had SNPs represented on the panel. We performed random forests (RF) analyses of SNPs within each pathway group and logistic regression to assess interaction among genes in the one pathway for which the RF prediction error was better than chance and the permutation P < 0.10. Only the DNA repair pathway had a better than chance classification of case-control status with a prediction error of 45.5% and P = 0.09. Three SNPs (rs1047840 of EXO1, rs12450550 of EME1, and rs799917 of BRCA1) of the DNA repair pathway were identified as promising candidates for further replication. In addition, statistically significant interactions (P < 0.05) between rs1047840 of EXO1 and rs799917 or rs1799966 of BRCA1 were observed. Despite less than complete inclusion of genes and SNPs relevant to glioma and a small sample size, RF analysis identified one important biological pathway and several SNPs potentially associated with the development of glioblastoma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1368–73)

Distinct germ line polymorphisms underlie glioma morphologic heterogeneity

Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports, it was not clear whether the single nucleotide polymorphism associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case-control groups composed of the spectrum of infiltrating glioma subtypes and stratified the analyses by type. We report that specific germ line polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, odds ratio [OR] = 2.05, P = 8.3 × 10(-11)) but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms, which are significantly associated with glioblastoma (rs2297440, OR = 0.56, P = 4.6 × 10(-10)) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR = 2.77, P = 2.6 × 10(-9)). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.

Effects of antihistamine and anti-inflammatory medication use on risk of specific glioma histologies.

Several studies have shown a decrease in glioma risk associated with a personal history of allergic conditions and the medications used to treat the symptoms. However, few studies have been able to examine risk within histological subgroups of glioma. Case–control data from M. D. Anderson Cancer Center and University of California, San Francisco were pooled to conduct the analysis stratified by histological subtype. A risk prediction model considering inflammation‐related variables and antihistamine use was built using logistic regression. Of the subtypes examined, long‐term antihistamine use was associated with increased risk of anaplastic gliomas, especially when length of use was considered in conjunction with history of asthma or allergy. Anaplastic cases with no history of asthma or allergy were 2.94 times more likely than controls to report antihistamine use for 10 years or more; whereas anaplastic cases with a history of asthma or allergy were 2.34 times more likely than controls to report antihistamine use for 10 years or more. Furthermore, anti‐inflammatory medication use was associated with a protective effect against glioblastoma (OR = 0.80; 95% CI: 0.65, 0.99), especially among individuals with no history of asthma or allergies. No statistically significant effects of anti‐inflammatory drugs or antihistamines were evident for the other histological subtypes. Thus, modulation of the immune system by the use of common drugs, such as antihistamines or nonsteroidal anti‐inflammatory drugs, may contribute to the development of certain types of brain tumors.