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Authors:
Melin BS, Barnholtz-Sloan JS, Wrensch MR
Abstract
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.
PMID:
28346443
[PubMed - as supplied by publisher]
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Neuro-oncology 2016 Dec 29
Authors:
Reardon DA, Lassman AB, van den Bent M, Kumthekar P, Merrell R, Scott AM, Fichtel L, Sulman EP, Gomez E, Fischer J, Lee HJ, Munasinghe W, Xiong H, Mandich H, Roberts-Rapp L, Ansell P, Holen KD, Gan HK
Abstract
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).
In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O(6)-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.
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.
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).
PMID:
28039367
[PubMed - as supplied by publisher]
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Authors:
Amirian ES, Scheurer ME, Zhou R, Wrensch MR, Armstrong GN, Lachance D, Olson SH, Lau CC, Claus EB
Abstract
Varicella zoster virus (VZV) is a neurotropic α-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted.
PMID:
26972449
[PubMed - as supplied by publisher]
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Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2016 Feb
Authors:
Amirian ES, Zhou R, Wrensch MR, Olson SH, Scheurer ME, Il'yasova D, Lachance D, Armstrong GN, McCoy LS, Lau CC, Claus EB, Barnholtz-Sloan JS, Schildkraut J, Ali-Osman F, Sadetzki S, Johansen C, Houlston RS, Jenkins RB, Bernstein JL, Merrell RT, Davis FG, Lai R, Shete S, Amos CI, Melin BS, Bondy ML
Abstract
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.
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.
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.
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.
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.
PMID:
26908595
[PubMed - as supplied by publisher]
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American journal of epidemiology 2016 Jan 15
Authors:
Amirian ES, Armstrong GN, Zhou R, Lau CC, Claus EB, Barnholtz-Sloan JS, Il'yasova D, Schildkraut J, Ali-Osman F, Sadetzki S, Johansen C, Houlston RS, Jenkins RB, Lachance D, Olson SH, Bernstein JL, Merrell RT, Wrensch MR, Davis FG, Lai R, Shete S, Amos CI, Scheurer ME, Aldape K, Alafuzoff I, Brännström T, Broholm H, Collins P, Giannini C, Rosenblum M, Tihan T, Melin BS, Bondy ML
Abstract
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.
PMID:
26656478
[PubMed - as supplied by publisher]
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Scientific reports 2015 Feb 05
Authors:
Jalali A, Amirian ES, Bainbridge MN, Armstrong GN, Liu Y, Tsavachidis S, Jhangiani SN, Plon SE, Lau CC, Claus EB, Barnholtz-Sloan JS, Il'yasova D, Schildkraut J, Ali-Osman F, Sadetzki S, Johansen C, Houlston RS, Jenkins RB, Lachance D, Olson SH, Bernstein JL, Merrell RT, Wrensch MR, Davis FG, Lai R, Shete S, Aldape K, Amos CI, Muzny DM, Gibbs RA, Melin BS, Bondy ML
Abstract
Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned.
PMID:
25652157
[PubMed - as supplied by publisher]
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Journal of the National Cancer Institute 2015 Jan
Authors:
Bainbridge MN, Armstrong GN, Gramatges MM, Bertuch AA, Jhangiani SN, Doddapaneni H, Lewis L, Tombrello J, Tsavachidis S, Liu Y, Jalali A, Plon SE, Lau CC, Parsons DW, Claus EB, Barnholtz-Sloan J, Il'yasova D, Schildkraut J, Ali-Osman F, Sadetzki S, Johansen C, Houlston RS, Jenkins RB, Lachance D, Olson SH, Bernstein JL, Merrell RT, Wrensch MR, Walsh KM, Davis FG, Lai R, Shete S, Aldape K, Amos CI, Thompson PA, Muzny DM, Gibbs RA, Melin BS, Bondy ML, Gliogene Consortium
Abstract
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.
PMID:
25482530
[PubMed - as supplied by publisher]
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Authors:
Andersson U, Wibom C, Cederquist K, Aradottir S, Borg A, Armstrong GN, Shete S, Lau CC, Bainbridge MN, Claus EB, Barnholtz-Sloan J, Lai R, Il'yasova D, Houlston RS, Schildkraut J, Bernstein JL, Olson SH, Jenkins RB, Lachance DH, Wrensch M, Davis FG, Merrell R, Johansen C, Sadetzki S, Gliogene Consortium, Bondy ML, Melin BS
Abstract
Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers.
Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma.
We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer.
Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.
PMID:
24723567
[PubMed - as supplied by publisher]
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Clinical neurology and neurosurgery 2014 Feb
Authors:
Shakur SF, Bit-Ivan E, Watkin WG, Merrell RT, Farhat HI
Abstract
Glioblastoma (GBM) rarely presents as an infratentorial tumor in adults. The authors present a case of concomitant supratentorial and infratentorial GBM in an adult. A 72-year-old man presented with headache, nausea, vomiting, and lightheadedness. Initial MR images revealed enhancing masses in the right cerebellum and right posterior periventricular region. The patient underwent a suboccipital craniotomy and resection of the cerebellar lesion. Final histopathology was consistent with glioblastoma. The patient went on to receive standard radiation treatment for GBM with concurrent and adjuvant temozolomide. However, the patient experienced clinical deterioration within a few days after starting radiotherapy. He and his family decided to forego treatment and pursue palliative care. The patient expired three months after the initial diagnosis. Autopsy findings supported the diagnosis of GBM with leptomeningeal gliomatosis and involvement of the cerebrum, cerebellum, and spinal cord. The authors review the literature and propose that the pathogenesis of multiple and multicentric GBM may involve neural stem cells within the subventricular zone or could result from tumor dissemination along established CNS routes, such as white matter tracts and CSF pathways.
PMID:
24438802
[PubMed - as supplied by publisher]