11 results on '"Hawkins, Cynthia"'
Search Results
2. An update on the CNS manifestations of brain tumor polyposis syndromes.
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Kim, Byungjin, Tabori, Uri, and Hawkins, Cynthia
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BRAIN tumors , *LI-Fraumeni syndrome , *GASTROINTESTINAL cancer , *SYNDROMES ,CENTRAL nervous system tumors - Abstract
Cancer predisposition syndromes are associated with an increased risk of developing primary malignancies. Here we discuss those which are associated with an increased risk of tumors of the central nervous system (CNS) and gastrointestinal (GI) tract. These can be grouped into those in which the CNS tumors predominate versus those in which the GI cancers predominate. The former include constitutional mismatch repair deficiency (CMMRD) syndrome, Li–Fraumeni syndrome (LFS), and Cowden syndrome (CS) while the latter include familial adenomatosis polyposis 1 (FAP1), Lynch syndrome and polymerase proofreading-associated polyposis syndrome (PPAP). Tumor specificity does exist as medulloblastoma occur in FAP, LFS and CMMRD while glioma are most commonly seen in all replication repair-deficient genes and LFS. Choroid plexus carcinoma is strictly observed in LFS while Cowden syndrome patients develop Lhermitte Duclos disease or meningioma. In each syndrome, specific types of low-grade and high-grade gastrointestinal cancers can occur, but these will be discussed elsewhere. Underlying cancer predisposition syndromes are important to consider when faced with brain tumors, particularly in the pediatric and young adult age groups, as identification of an underlying germ line mutation may change the upfront management of the patient and has implications for future cancer surveillance for both the patient and potentially affected family members. Considerations of family history, presence of skin lesions and consanguinity provide valuable information in identifying patients at potential increased risk. [ABSTRACT FROM AUTHOR]
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- 2020
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3. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.
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Tatari, Nazanin, Khan, Shahbaz, Livingstone, Julie, Zhai, Kui, Mckenna, Dillon, Ignatchenko, Vladimir, Chokshi, Chirayu, Gwynne, William D., Singh, Manoj, Revill, Spencer, Mikolajewicz, Nicholas, Zhu, Chenghao, Chan, Jennifer, Hawkins, Cynthia, Lu, Jian-Qiang, Provias, John P., Ask, Kjetil, Morrissy, Sorana, Brown, Samuel, and Weiss, Tobias
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PROTEOMICS , *GLIOBLASTOMA multiforme , *SYMPTOMS , *DRUG target - Abstract
Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM–rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2–5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma.
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Siddaway, Robert, Canty, Laura, Pajovic, Sanja, Milos, Scott, Coyaud, Etienne, Sbergio, Stefanie-Grace, Vadivel Anguraj, Arun Kumaran, Lubanszky, Evan, Yun, Hwa Young, Portante, Alessia, Carette, Sheyenne, Zhang, Cunjie, Moran, Michael F., Raught, Brian, Campos, Eric I., and Hawkins, Cynthia
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DRUG target , *GLIOMAS , *TRANSCRIPTION factors , *DNA repair , *CHROMATIN , *METHYLGUANINE , *CATECHOL-O-methyltransferase , *METHYLTRANSFERASES - Abstract
Histone H3 mutations at amino acids 27 (H3K27M) and 34 (H3G34R) are recurrent drivers of pediatric-type high-grade glioma (pHGG). H3K27M mutations lead to global disruption of H3K27me3 through dominant negative PRC2 inhibition, while H3G34R mutations lead to local losses of H3K36me3 through inhibition of SETD2. However, their broader oncogenic mechanisms remain unclear. We characterized the H3.1K27M, H3.3K27M and H3.3G34R interactomes, finding that H3K27M is associated with epigenetic and transcription factor changes; in contrast H3G34R removes a break on cryptic transcription, limits DNA methyltransferase access, and alters mitochondrial metabolism. All 3 mutants had altered interactions with DNA repair proteins and H3K9 methyltransferases. H3K9me3 was reduced in H3K27M-containing nucleosomes, and cis-H3K9 methylation was required for H3K27M to exert its effect on global H3K27me3. H3K9 methyltransferase inhibition was lethal to H3.1K27M, H3.3K27M and H3.3G34R pHGG cells, underscoring the importance of H3K9 methylation for oncohistone-mutant gliomas and suggesting it as an attractive therapeutic target. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers.
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Ichimura, Koichi, Narita, Yoshitaka, and Hawkins, Cynthia
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ASTROCYTOMAS , *PATHOLOGY , *TUMORS , *MOLECULAR pathology , *ISOCITRATE dehydrogenase , *GLIOBLASTOMA multiforme - Abstract
Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of WHO grade have concurrent mutations of IDH1 or IDH2, TP53 and ATRX. Among these astrocytomas, no other genetic markers that may distinguish grade II and grade III tumours have been identified. Those astrocytomas without IDH mutation tend to have a distinct genotype and a poor prognosis comparable to that of glioblastomas. On the other hand, diffuse astrocytomas that arise in children do not harbour IDH/ TP53 mutations, but instead display mutations of BRAF or structural alterations involving MYB/ MYBL1 or FGFR1. A molecular classification may thus help delineate diffusely infiltrating astrocytomas into distinct pathogenic and prognostic groups, which could aid in determining individualised therapeutic strategies. [ABSTRACT FROM AUTHOR]
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- 2015
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6. BRAF alteration status and the histone H3F3A gene K27M mutation segregate spinal cord astrocytoma histology.
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Shankar, Ganesh, Lelic, Nina, Gill, Corey, Thorner, Aaron, Hummelen, Paul, Wisoff, Jeffrey, Loeffler, Jay, Brastianos, Priscilla, Shin, John, Borges, Lawrence, Butler, William, Zagzag, David, Brody, Rachel, Duhaime, Ann-Christine, Taylor, Michael, Hawkins, Cynthia, Louis, David, Cahill, Daniel, Curry, William, and Meyerson, Matthew
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BRAF genes , *SUPRATENTORIAL brain tumors , *GLIOMAS , *MOLECULAR oncology , *CHROMOSOME abnormalities - Abstract
The article discusses a study related to supratentorial gliomas which reveals discrete genomic alterations to discriminate discriminate pilocytic astrocytomas, diffuse gliomas, and glioblastoma. Topics discussed includes co-deletion of chromosomes not revealed by loss of heterozygosity analysis for variant allele frequency, assess for the changes by transcriptional analysis of spinal cord astrocytomas, and success in BRAF-mutant cancer types with the BRAFâ€MEK inhibitors.
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- 2016
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7. Announcing cIMPACT-NOW: the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy.
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Louis, David, Aldape, Ken, Brat, Daniel, Capper, David, Ellison, David, Hawkins, Cynthia, Paulus, Werner, Perry, Arie, Reifenberger, Guido, Figarella-Branger, Dominique, Wesseling, Pieter, Batchelor, Tracy, Cairncross, J., Pfister, Stefan, Rutkowski, Stefan, Weller, Michael, Wick, Wolfgang, and Deimling, Andreas
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TUMORS , *CENTRAL nervous system - Abstract
The author discusses the publication of the "2016 World Health Organization Classification of Tumors of the Central Nervous System" (2016 CNS WHO) which represents the advancement of the classification of human brain tumors and facilitates a precise diagnosis of well-understood entities.
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- 2017
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8. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications.
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Buczkowicz, Pawel, Bartels, Ute, Bouffet, Eric, Becher, Oren, and Hawkins, Cynthia
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GLIOMAS , *GLIOMA treatment , *BRAIN tumors , *CHILD mortality , *TUMORS in children , *DIAGNOSIS - Abstract
Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II-IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III-IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II-IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas. [ABSTRACT FROM AUTHOR]
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- 2014
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9. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma.
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Dubuc, Adrian, Remke, Marc, Korshunov, Andrey, Northcott, Paul, Zhan, Shing, Mendez-Lago, Maria, Kool, Marcel, Jones, David, Unterberger, Alexander, Morrissy, A., Shih, David, Peacock, John, Ramaswamy, Vijay, Rolider, Adi, Wang, Xin, Witt, Hendrik, Hielscher, Thomas, Hawkins, Cynthia, Vibhakar, Rajeev, and Croul, Sidney
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MEDULLOBLASTOMA , *HISTONES , *LYSINE , *METHYLATION , *NUCLEOTIDES , *GENETIC mutation - Abstract
Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27−) and dismal (K4−/K27−) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation ( EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease. [ABSTRACT FROM AUTHOR]
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- 2013
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10. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples.
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Northcott, Paul, Shih, David, Remke, Marc, Cho, Yoon-Jae, Kool, Marcel, Hawkins, Cynthia, Eberhart, Charles, Dubuc, Adrian, Guettouche, Toumy, Cardentey, Yoslayma, Bouffet, Eric, Pomeroy, Scott, Marra, Marco, Malkin, David, Rutka, James, Korshunov, Andrey, Pfister, Stefan, and Taylor, Michael
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MEDULLOBLASTOMA , *MOLECULAR oncology , *PROTEIN microarrays , *MEDICAL experimentation on humans , *DIAGNOSIS - Abstract
The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials. [ABSTRACT FROM AUTHOR]
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- 2012
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11. Cribriform neuroepithelial tumour: novel clinicopathological, ultrastructural and cytogenetic findings.
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Ibrahim, George, Huang, Annie, Halliday, William, Dirks, Peter, Malkin, David, Baskin, Berivan, Shago, Mary, and Hawkins, Cynthia
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CASE studies , *NAUSEA , *TOMOGRAPHY , *MAGNETIC resonance imaging , *IMMUNOHISTOCHEMISTRY ,EPITHELIAL cell tumors - Abstract
The article presents a case study of a 21-month-old boy presented with a one-week history of various disorders including recurrent falls, imbalance, and progressive nausea. The patients' clinical examinations including computed tomography (CT) scan, magnetic resonance (MR) imaging, and immunohistochemistry led to the diagnosis of cribriform neuroepithelial tumour (CRINET). It also discusses CRINET, which is defined as a tumour of neuroectodermal origin with distinct cribriform.
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- 2011
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