Ryan Merrell

Germline mutations in shelterin complex genes are associated with familial glioma

Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

Blood pressure fluctuations in posterior reversible encephalopathy syndrome.

BACKGROUND Posterior reversible encephalopathy syndrome (PRES) can be a consequence of hypertensive crisis and is often associated with rapid fluctuations in blood pressure (BP). However, the role of these BP changes in the pathogenesis of PRES has not been formally studied. Our objective was to analyze the relationship between BP fluctuations and the occurrence of PRES. METHODS We identified consecutive patients who developed PRES in the hospital and compared them with randomly selected controls matched for age, gender, and history of hypertension (HTN). Systolic BP (SBP) and diastolic BP (DBP) were collected at 2-hour intervals over a 48-hour window before the onset of PRES symptoms. A profile of changes in the values of SBP, DBP, mean arterial pressure (MAP), and pulse pressure (PP) over the 48-hour window was summarized for each individual by calculating a single number (M value) using the approach by Service et al. Comparisons of these summary numbers between the 2 groups (cases and controls) were made with the Wilcoxon signed rank test because of the smaller sample size and paired nature of the data. All tests were 2-sided, and P < .05 was considered statistically significant. RESULTS We analyzed the BP profiles in 25 cases of PRES and 25 controls. The median age of PRES patients was 54 years (range 31-72). Fourteen of them (56%) had a history of HTN. Hypertensive encephalopathy was considered the underlying cause of PRES in 13 patients (52%). At the time of the first symptoms of PRES, the mean SBP was 182 ± 20 mm Hg (range 218-145), DBP 95 ± 16 mm Hg (range 134-62), MAP 124 ± 15 (range 152-93), and PP 87 ± 18 (range 123-46). While BP was higher in PRES cases, the severity of HTN was variable and BP fluctuations were not significantly more common than in controls (P = .38 for SBP, .79 for DBP, .25 for MAP, and .73 for PP, respectively). CONCLUSIONS Although acute HTN is frequent in patients with PRES, BP fluctuations do not appear to be more common in hospitalized patients who develop PRES compared with controls matched for age and history of HTN. Other predisposing factors must therefore contribute to the development of PRES.

Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.

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.

Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma

Background The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR). Methods In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model. Results As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39% harbored EGFR amplification, of which 73% had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30% showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached. Conclusion ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Seizures in patients with glioma treated with phenytoin and levetiracetam

e13020 Background: Seizures are common in patients with glioma. Phenytoin, traditionally used for these patients, can be associated with intolerable side effects and potentially alters the metabolism of chemotherapeutic agents. Levetiracetam has more favorable pharmacokinetics facilitating ease of use with fewer side effects and is nonenzyme inducing. We compare seizure outcomes and side effects in patients with glioma treated with phenytoin and levetiracetam monotherapy. METHODS Retrospective analysis of consecutive patients with glioma. Subjects had at least one clinical seizure and had to be followed for 6 months. Seizure outcomes and side effects were compared between cohorts treated with phenytoin or levetiracetam. Seizure outcomes were measured by time to second seizure and seizure frequency. RESULTS 76 patients (34 female) with pathologically proven glioma and seizures were identified, 25 treated with phenytoin and 51 with levetiracetam. 64% had grade 4 astrocytoma. There was no difference in seizure outcome between the phenytoin and levetiracetam groups when comparing time to second seizure (p = 0.584), second seizure rates (p = 0.462), and average seizures per month (p = 0.776). When adjusting for age, gender, type of seizure, type of glioma, and dosage using univariate and multivariate models there were no differences between the treatment groups and none of these covariates were statistically significant for explaining the second seizure rates between treatment groups (all p values >0.05). The incidence of side effects in the levetiracetam group was 5.9% versus 20% in the phenytoin group (p = 0.106). Additionally, 36.0% of the patients in the phenytoin group had dose adjustments not related to breakthrough seizures compared to only 9.8% in the levetiracetam group (p = 0.010). CONCLUSIONS In this study, glioma patients treated with levetiracetam had similar seizure control as patients treated with phenytoin. Patients treated with levetiracetam experienced fewer side effects and required fewer non seizure related dose adjustments than patients treated with phenytoin. Levetiracetam is a safe, effective, and preferred alternative for seizure management in patients with glioma. No significant financial relationships to disclose.OBJECT Second-generation antiepileptic drugs (AEDs) are increasingly used in the care of patients with glioma. There is little data on how this practice compares with the use of traditional AEDs in this population. This noninferiority analysis compares seizure outcomes and side effects in patients with glioma treated with phenytoin and levetiracetam monotherapy. METHODS The authors retrospectively reviewed the records of 500 consecutive patients with glioma who were treated in clinical trials from 2001 to 2008 at 3 Mayo Clinic campuses. To be eligible for the study, these patients had to have had at least 1 clinical seizure and to have undergone follow-up for at least 6 months. Seizure outcomes, defined by the occurrence of a second seizure, time to second seizure, and seizure frequency, along with AED side effects, were compared between cohorts treated with phenytoin or levetiracetam RESULTS Seventy-six patients were identified, 25 treated with phenytoin and 51 with levetiracetam. Sixty-four percent of the patients had a Grade 4 astrocytoma. There was no difference in seizure outcome between the phenytoin and levetiracetam groups when comparing time to second seizure (p=0.584), second seizure rates (p=0.561), and average seizures per month (p=0.776). When adjusting for age, sex, type of seizure, type of glioma, and dosage using univariate and multivariate models, there were no differences between the treatment groups and none of these covariates were statistically significant for explaining the second seizure rates between treatment groups (all p values>0.05). The incidence of side effects in the levetiracetam group was 6% versus 20% in the phenytoin group (p=0.106). Additionally, 36% of the patients in the phenytoin group had dose adjustments unrelated to breakthrough seizures compared with only 10% in the levetiracetam group (p=0.010) CONCLUSIONS In this study, patients with glioma treated with levetiracetam and phenytoin had similar seizure control. Patients treated with levetiracetam experienced fewer side effects and required fewer nonseizure-related dose adjustments than patients treated with phenytoin. Levetiracetam is a safe, effective, and preferred alternative for seizure management in patients with glioma.

Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study

Background: Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. Methods: The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Results: Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58–0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. Conclusion: A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. Impact: As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. Cancer Epidemiol Biomarkers Prev; 25(2); 282–90. ©2016 AACR.

Description of selected characteristics of familial glioma patients – Results from the Gliogene Consortium

BACKGROUND While 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. METHODS Families 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. FINDINGS The 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 <40y, and in 12% both were diagnosed under 40y of age. Most of these families (76%) had at least one grade IV glioblastoma multiforme (GBM), and in 32% both cases were grade IV gliomas. The most common glioma subtype was GBM (55%), followed by anaplastic astrocytoma (10%) and oligodendroglioma (8%). Individuals with grades I-II were on average 17y younger than those with grades III-IV. INTERPRETATION Familial glioma cases are similar to sporadic cases in terms of gender distribution, age, morphology and grade. Most familial gliomas appear to comprise clusters of two cases suggesting low penetrance, and that the risk of developing additional gliomas is probably low. These results should be useful in the counselling and clinical management of individuals with a family history of glioma.

1p/19q chromosome deletions in metastatic oligodendroglioma

Extracranial metastasis of primary brain tumors is a rare phenomenon. Of the few cases reported of metastatic oligodendroglioma, only two have evaluated genetic alterations, specifically deletions of chromosomes 1p and 19q. Herein, we report two additional patients with metastatic anaplastic oligodendroglioma to bone, both followed until death. All available pathology specimens were reviewed and genetic analysis was performed in one of the cases. Although the bone metastasis was non-informative, the primary intracranial tumor revealed codeletions of the 1p and 19q chromosomal arms, commonly recognized as the genetically favorable profile of oligodendrogliomas. Both patients died of complications related to their systemic disease and did not have any radiologic evidence of intracranial progression at the time of their last MRI studies. Along with the reported literature, our data suggest that despite their generally favorable behavioral profiles, oligodendroglial tumors with 1p/19q deletions may be more prone to metastasis as they progress. Genetic analysis serves a valuable ancillary role in the diagnostic workup of such cases.

The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium

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.

A variable age of onset segregation model for linkage analysis, with correction for ascertainment, applied to glioma.

Background: We propose a 2-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma. Methods: First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N = 281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N = 74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are reestimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis. Results: Using the best-fitting segregation models in model-based multipoint linkage analysis, we identified 2 separate peaks on chromosome 17; the first agreed with a region identified by Shete and colleagues who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum log of the odds (LOD). Conclusions: Our approach was able to narrow the linkage peak previously published for glioma. Impact: We provide a practical solution to model-based linkage analysis for disease affection status with variable age of onset for the kinds of pedigree data often collected for linkage analysis. Cancer Epidemiol Biomarkers Prev; 21(12); 2242–51. ©2012 AACR.