A Variable Age of Onset Segregation Model for Linkage Analysis, with Correction for Ascertainment, Applied to Glioma
BACKGROUND: We propose a two-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 re-estimated 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 two separate peaks on chromosome 17; the first agreed with a region identified by Shete et al. (1) 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 LOD. Conclusions/Impact: Our approach has the advantage of not requiring markers to be in linkage equilibrium unless the minor allele frequency is small (markers which tend to be uninformative for linkage), and of using more of the available information for LOD-based linkage analysis.
Available from: Judith Schwartzbaum
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ABSTRACT: Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O(6)-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine-phosphate-guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a "state of the science" review of current research into causes and risk factors for gliomas in adults.
Neuro-Oncology 05/2014; 16(7). DOI:10.1093/neuonc/nou087 · 5.56 Impact Factor
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To explore the clinical manifestations and imaging characteristics of gliomatosis cerebri to raise the awareness and improve its diagnostic accuracy for patients.
Materials and methods:
Clinical data, imaging characteristics and pathological examination of 12 patients with GC from Jan., 2008 to Jan., 2012 were analyzed retrospectively.
Patients with GC were clinically manifested with headache, vomiting, repeated seizures, fatigue and unstable walking, most of whom had more than 2 lesions involving in parietal lobe, followed by temporal lobe, frontal lobe, periventricular white matter and corpus callosum. Magnetic resonance imaging (MRI) showed diffuse distribution, T1-weighted images (T1WI) with equal and low signals and T2-weighted images (T2WI) with bilateral symmetrical high diffuse signals. There was no reinforcement by enhancement scanning and signals were different in diffusion-weighted images (DWI). The higher the tumor staging, the stronger the signals. Pathological examination showed neuroastrocytoma in which tumor tissues were manifested by infiltrative growth in blood vessels and around neurons.
In clinical diagnosis of GC, much attention should be paid to the diffuse distribution of imaging characteristics, incomplete matching between clinical and imaging characteristics and confirmation by combining with histopathological examination.
Asian Pacific journal of cancer prevention: APJCP 06/2014; 15(11):4487-91. DOI:10.7314/APJCP.2014.15.11.4487 · 2.51 Impact Factor
Available from: Markus Weiler
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ABSTRACT: Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.
Oncotarget 01/2015; DOI:10.18632/oncotarget.2910 · 6.36 Impact Factor
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