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Annekathrin Reinhardt, Damian Stichel, Daniel Schrimpf, Felix Sahm, Andrey Korshunov, David E Reuss, Christian Koelsche, Kristin Huang, Annika K Wefers, Volker Hovestadt, Martin Sill, Dorothee Gramatzki, Joerg Felsberg, Guido Reifenberger, Arend Koch, Ulrich-W Thomale, Albert Becker, Volkmar H Hans, Marco Prinz, Ori Staszewski, Till Acker, Hildegard Dohmen, Christian Hartmann, Wolf Mueller, Muin S A Tuffaha, Werner Paulus, Katharina Heß, Benjamin Brokinkel, Jens Schittenhelm, Camelia-Maria Monoranu, Almuth Friederike Kessler, Mario Loehr, Rolf Buslei, Martina Deckert, Christian Mawrin, Patricia Kohlhof, Ekkehard Hewer, Adriana Olar, Fausto J Rodriguez, Caterina Giannini, Amulya A NageswaraRao, Uri Tabori, Nuno Miguel Nunes, Michael Weller, Ute Pohl, Zane Jaunmuktane, Sebastian Brandner, Andreas Unterberg, Daniel Hänggi, Michael Platten, Stefan M Pfister, Wolfgang Wick, Christel Herold-Mende, David T W Jones, Andreas von Deimling, David Capper
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas...
March 21, 2018: Acta Neuropathologica
Akane Yamamichi, Fumiharu Ohka, Kosuke Aoki, Hiromichi Suzuki, Akira Kato, Masaki Hirano, Kazuya Motomura, Kuniaki Tanahashi, Lushun Chalise, Sachi Maeda, Toshihiko Wakabayashi, Yukinari Kato, Atsushi Natsume
The IDH-mutant and 1p/19q co-deletion (1p19q codel) provides significant diagnostic and prognostic value in lower-grade gliomas. As ATRX mutation and 1p19q codel are mutually exclusive, ATRX immunohistochemistry (IHC) may substitute for 1p19q codel, but this has not been comprehensively examined. In the current study, we performed ATRX-IHC in 78 gliomas whose ATRX statuses were comprehensively determined by whole exome sequencing. Among the 60 IHC-positive and 18 IHC-negative cases, 86.7 and 77.8% were ATRX-wildtype and ATRX-mutant, respectively...
March 17, 2018: Brain Tumor Pathology
Hong-Qing Cai, Peng-Fei Wang, Hai-Peng Zhang, Zhi-Jian Cheng, Shou-Wei Li, Jie He, Yu Zhang, Jia-Jie Hao, Ming-Rong Wang, Chang-Xiang Yan, Jing-Hai Wan
AIM: To identify biomarkers for accurate classification of glioma. PATIENTS AND METHODS: We evaluated the heat shock protein 27 (Hsp27), phosphorylated Hsp27 (p-Hsp27), ATRX and IDH1R132H proteins using immunohistochemistry in 421 glioma tissues. The χ2 test was used to assess the relationship between molecular alterations and clinico-pathological parameters. Kaplan-Meier survival curves were constructed, and differences were detected by the log-rank test. RESULTS: We found that Hsp27 and p-Hsp27 were mainly expressed in aggressive astrocytic gliomas...
March 17, 2018: Journal of Clinical Pathology
Zachary J Reitman, Frank Winkler, Andrew E H Elia
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. The current standard of care for GBM is maximal resection followed by postoperative radiation with concomitant and adjuvant temozolomide. Despite this multimodality treatment, the median survival for GBM remains marginally better than 1 year. In the past decade, genome-wide analyses have uncovered new molecular features of GBM that have refined its classification and provided new insights into the molecular basis for GBM pathogenesis...
February 2018: Seminars in Neurology
Joydeep Mukherjee, Tor-Christian Aase Johannessen, Shigeo Ohba, Tracy T Chow, Lindsey E Jones, Ajay Pandita, Russell O Pieper
A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower-grade astrocytomas (LGA) and secondary glioblastoma, we examined an hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis...
March 15, 2018: Cancer Research
Carla Danussi, Promita Bose, Prasanna T Parthasarathy, Pedro C Silberman, John S Van Arnam, Mark Vitucci, Oliver Y Tang, Adriana Heguy, Yuxiang Wang, Timothy A Chan, Gregory J Riggins, Erik P Sulman, Frederick Lang, Chad J Creighton, Benjamin Deneen, C Ryan Miller, David J Picketts, Kasthuri Kannan, Jason T Huse
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile...
March 13, 2018: Nature Communications
Takuya Furuta, Hiroaki Miyoshi, Satoru Komaki, Fumiko Arakawa, Motohiro Morioka, Koichi Ohshima, Mitsutoshi Nakada, Yasuo Sugita
Epithelioid glioblastoma (eGBM) is a rare variant of GBM which was adopted in the 2016 WHO classification. eGBM and pleomorphic xanthoastrocytoma (PXA) sometimes show overlapping features histologically and genetically, such as epithelioid pattern and a highly frequent V600E mutation in the gene for vRAF murine sarcoma viral oncogene homolog B1 (BRAF), respectively. Accurate diagnosis of these rare tumors is challenging according to the new criteria in the revised 2016 WHO classification. It is an urgent task to elucidate the biological properties of the tumors and to select appropriate treatment...
March 13, 2018: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Debajyoti Chatterjee, Bishan Dass Radotra, Narendra Kumar, Rakesh Kumar Vasishta, Sunil Kumar Gupta
Background: According to the current World Health Organization (WHO) classification of central nervous system (CNS) tumors (2016), histological diagnosis of gliomas should be supplemented by molecular information. This study was carried out to determine the frequency of isocitrate dehydrogenase 1 ( IDH 1), ATRX , and BRAF V600E mutations in different grade astrocytomas and their prognostic value. Methods: Eighty cases of astrocytoma (15 pilocytic astrocytoma, 25 diffuse astrocytoma, 15 anaplastic astrocytoma, and 25 glioblastoma) with follow-up information were analyzed using immunohistochemistry for IDH1 mutant protein, ATRX, p53, and BRAF...
2018: Surgical Neurology International
David R Martin, Elisa LaBauve, Joseph M Pomo, Vi K Chiu, Joshua A Hanson, Rama R Gullapalli
The major categories of pancreatic neuroendocrine tumor (PanNET) are well-differentiated NET and poorly differentiated neuroendocrine carcinoma. Sequencing of these tumors has identified multiple important genes in the pathogenesis of PanNETs, such as DAXX/ATRX, MEN1, TP53, RB, and mTOR pathway genes. We identified a case of well-differentiated PanNET with high-grade progression with simultaneous low- and high-grade histologic regions containing variable genomic profiles. We performed tumor microdissection and analyzed both regions using a 409-gene comprehensive cancer panel using next-generation sequencing in addition to immunohistochemical and morphologic studies...
April 2018: Pancreas
José E Velázquez Vega, Daniel J Brat
Recent advances in molecular pathology have reshaped the practice of brain tumor diagnostics. The classification of gliomas has been restructured with the discovery of isocitrate dehydrogenase (IDH) 1/2 mutations in the vast majority of lower grade infiltrating gliomas and secondary glioblastomas (GBM), with IDH-mutant astrocytomas further characterized by TP53 and ATRX mutations. Whole-arm 1p/19q codeletion in conjunction with IDH mutations now define oligodendrogliomas, which are also enriched for CIC, FUBP1, PI3K, NOTCH1, and TERT-p mutations...
March 8, 2018: Advances in Anatomic Pathology
Leomar Y Ballester, Zain Boghani, David S Baskin, Gavin W Britz, Randall Olsen, Gregory N Fuller, Suzanne Z Powell, Matthew D Cykowski
Astrocytes with multiple micronuclei ("Creutzfeldt cells") in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high-grade glioma versus tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood...
March 6, 2018: Brain Pathology
Somak Roy, William A LaFramboise, Ta-Chiang Liu, Dengfeng Cao, Alyssa Luvison, Caitlyn Miller, Maureen A Lyons, Roderick J O'Sullivan, Amer H Zureikat, Melissa E Hogg, Allan Tsung, Kenneth K Lee, Nathan Bahary, Randall E Brand, Jennifer S Chennat, Kenneth E Fasanella, Kevin McGrath, Marina N Nikiforova, Georgios I Papachristou, Adam Slivka, Herbert J Zeh, Aatur D Singhi
Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and ATRX chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed...
February 24, 2018: Gastroenterology
Jonathan Nye, Daniël P Melters, Yamini Dalal
Histone chaperones are indispensable regulators of chromatin structure and function. Recent work has shown that they are frequently mis-regulated in cancer, which can have profound consequences on tumor growth and survival. Here, we focus on chaperones for the essential H3 histone variants H3.3 and CENP-A, specifically HIRA, DAXX/ATRX, DEK, and HJURP. This review summarizes recent studies elucidating their roles in regulating chromatin and discusses how cancer-specific chromatin interactions can be exploited to target cancer cells...
2018: F1000Research
Johann-Martin Hempel, Jens Schittenhelm, Uwe Klose, Benjamin Bender, Georg Bier, Marco Skardelly, Ghazaleh Tabatabai, Salvador Castaneda Vega, Ulrike Ernemann, Cornelia Brendle
PURPOSE: To assess the diagnostic performance of dynamic susceptibility contrast perfusion magnetic resonance perfusion imaging (DSC-MRI) for in vivo human glioma molecular profiling. METHODS: In this study 100 patients with histopathologically confirmed glioma who provided written informed consent were retrospectively assessed between January 2016 and February 2017 in two prospective trials that were approved by the local institutional review board. Cerebral blood volume (CBV) measurements from DSC-MRI were assessed, and histogram parameters of relative CBV (rCBV) results were compared among World Health Organization (WHO) 2016 based histological findings and molecular characteristics...
February 21, 2018: Clinical Neuroradiology
Bianca Ho, Keelin Greenlaw, Abeer Al Tuwaijri, Sanny Moussette, Francisco Martínez, Elisa Giorgio, Alfredo Brusco, Giovanni Battista Ferrero, Natália D Linhares, Eugênia R Valadares, Marta Svartman, Vera M Kalscheuer, Germán Rodríguez Criado, Catherine Laprise, Celia M T Greenwood, Anna K Naumova
BACKGROUND: Sexual dimorphism in DNA methylation levels is a recurrent epigenetic feature in different human cell types and has been implicated in predisposition to disease, such as psychiatric and autoimmune disorders. To elucidate the genetic origins of sex-specific DNA methylation, we examined DNA methylation levels in fibroblast cell lines and blood cells from individuals with different combinations of sex chromosome complements and sex phenotypes focusing on a single autosomal region--the differentially methylated region (DMR) in the promoter of the zona pellucida binding protein 2 (ZPBP2) as a reporter...
February 20, 2018: Biology of Sex Differences
Tobias Hofving, Yvonne Arvidsson, Bilal Almobarak, Linda Inge, Roswitha Pfragner, Marta Persson, Göran Stenman, Erik Kristiansson, Viktor Johanson, Ola Nilsson
Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not...
March 2018: Endocrine-related Cancer
Yiming Li, Xing Liu, Zenghui Qian, Zhiyan Sun, Kaibin Xu, Kai Wang, Xing Fan, Zhong Zhang, Shaowu Li, Yinyan Wang, Tao Jiang
OBJECTIVES: To predict ATRX mutation status in patients with lower-grade gliomas using radiomic analysis. METHODS: Cancer Genome Atlas (TCGA) patients with lower-grade gliomas were randomly allocated into training (n = 63) and validation (n = 32) sets. An independent external-validation set (n = 91) was built based on the Chinese Genome Atlas (CGGA) database. After feature extraction, an ATRX-related signature was constructed. Subsequently, the radiomic signature was combined with a support vector machine to predict ATRX mutation status in training, validation and external-validation sets...
February 5, 2018: European Radiology
Marta Kovatcheva, Mary E Klein, William D Tap, Andrew Koff
Senescence is an irreversible form of growth arrest and is generally considered a favorable outcome of cancer therapies, yet little is known about the molecular events that distinguish this state from readily reversible growth arrest (i.e. quiescence). Recently, we discovered that during therapy induced senescence the chromatin remodeling protein α-thalassemia, mental retardation, X-linked (ATRX) represses Harvey rat sarcoma viral oncogene homolog ( HRAS) , and repression of HRAS is necessary to establish senescence, suggesting how new clinical combinations might be used to achieve durable senescence...
2018: Molecular & Cellular Oncology
Lea Kristin Röver, Heidrun Gevensleben, Jörn Dietrich, Friedrich Bootz, Jennifer Landsberg, Diane Goltz, Dimo Dietrich
Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas...
January 24, 2018: EBioMedicine
Takashi Komori, Yoshihiro Muragaki, Mikhail F Chernov
Current World Health Organization (WHO) classification of the neuroepithelial tumors is cell lineage-oriented and based on a presumed developmental tree of the central nervous system (CNS). It defines three main groups of gliomas, namely astrocytomas, oligodendrogliomas, and ependymomas, and additionally presumes their 4-tiered histopathological grading (WHO grades I to IV). Nevertheless, the impact of tumor pathology on clinically related parameters may be frequently much better predicted by genetics, than by histological appearance of the lesion...
2018: Progress in Neurological Surgery
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