CNS.Biomarker.template
Template for Reporting Results of Biomarker Testing of Specimens From Patients With Tumors of the Central Nervous SystemTemplate web posting date: December 2014AuthorsDaniel J?Brat, MD, PhD Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GeorgiaPhilip Cagle, MDDepartment of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TXDeborah Dillon, MDDepartment of Pathology, Brigham and Women's Hospital, Boston, MAEyas Hattab, MD Department of Pathology, Indiana University Medical Center, Indianapolis, IndianaRoger E. McLendon, MD Department of Pathology, Duke University Medical Center, Durham, NCMargaret A Miller, RHIT, CTRSaint Agnes Hospital, Baltimore, MDJan C Buckner, MDDepartment of Oncology, Mayo Clinic, Rochester, MNFor the Members of the Cancer Biomarker Reporting Committee, College of American Pathologists? 2014 College of American Pathologists (CAP). All rights reserved.The College does not permit reproduction of any substantial portion of these templates without its written authorization. The College hereby authorizes use of these templates by physicians and other health care providers in reporting results of biomarker testing on patient specimens, in teaching, and in carrying out medical research for nonprofit purposes. This authorization does not extend to reproduction or other use of any substantial portion of these templates for commercial purposes without the written consent of the College.The CAP also authorizes physicians and other health care practitioners to make modified versions of the templates solely for their individual use in reporting results of biomarker testing for individual patients, teaching, and carrying out medical research for non-profit purposes.The CAP further authorizes the following uses by physicians and other health care practitioners, in reporting on surgical specimens for individual patients, in teaching, and in carrying out medical research for non-profit purposes: (1) Dictation from the original or modified templates for the purposes of creating a text-based patient record on paper, or in a word processing document; (2) Copying from the original or modified templates into a text-based patient record on paper, or in a word processing document; (3) The use of a computerized system for items (1) and (2), provided that the template data is stored intact as a single text-based document, and is not stored as multiple discrete data fields.Other than uses (1), (2), and (3) above, the CAP does not authorize any use of the templates in electronic medical records systems, pathology informatics systems, cancer registry computer systems, computerized databases, mappings between coding works, or any computerized system without a written license from the CAP.Any public dissemination of the original or modified templates is prohibited without a written license from the CAP.The College of American Pathologists offers these templates to assist pathologists in providing clinically useful and relevant information when reporting results of biomarker testing. The College regards the reporting elements in the templates as important elements of the biomarker test report, but the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.The College developed these templates as educational tools to assist pathologists in the useful reporting of relevant information. It did not issue them for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the templates might be used by hospitals, attorneys, payers, and others. The College cautions that use of the templates other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.The inclusion of a product name or service in a CAP publication should not be construed as an endorsement of such product or service, nor is failure to include the name of a product or service to be construed as disapproval.CAP CNS Biomarker Template Revision HistoryVersion CodeThe definition of the version code can be found at cancerprotocols.Version: CNS_Biomarkers 1.0.0.0Summary of ChangesThis is a new template. CNS Biomarker Reporting TemplateTemplate web posting date: December 2014Completion of the template is the responsibility of the laboratory performing the biomarker testing and/or providing the interpretation. When both testing and interpretation are performed elsewhere (eg,?a reference laboratory), synoptic reporting of the results by the laboratory submitting the tissue for testing is also encouraged to ensure that all information is included in the patient’s medical record and thus readily available to the treating clinical team.CENTRAL NERVOUS SYSTEM (CNS)Select a single response unless otherwise indicated.Note: Use of this template is optional.+ RESULTS+ GLIOMAS + IDH1/2 Mutation+ ___ Present (specify): ________________________+ ___ Absent + ___ Cannot be determined (explain): ________________________+ IDH1 R132H Immunohistochemistry+ ___ Positive+ ___ Negative + ___ Cannot be determined (explain): ________________________+ 1p/19q Deletion + ___ 1p/19q co-deletion+ ___ 1p only deleted+ ___ 19q only deleted+ ___ Polysomy (specify): ________________________+ ___ Monosomy (specify): ________________________+ ___ None detected + ___ Cannot be determined (explain): ________________________+ TP53 Mutation+ ___ Present (specify): ________________________+ ___ Absent + ___ Cannot be determined (explain): ________________________+ ATRX Mutation+ ___ Present (specify): ________________________+ ___ Absent+ ___ Cannot be determined (explain): ________________________+ ATRX Immunohistochemistry + ___ Loss of nuclear expression + ___ Intact nuclear expression+ ___ Cannot be determined (explain): ________________________+ EGFR Amplification + ___ Present+ ___ Absent+ ___ Cannot be determined (explain): ________________________+ 10q23 (PTEN Locus) Deletion+ ___ Deletion identified+ ___ Polysomy (specify): ________________________+ ___ Monosomy (specify): ________________________+ ___ None detected+ ___ Cannot be determined (explain): ________________________+ PTEN Mutation+ ___ Present (specify): ________________________+ ___ Absent+ ___ Cannot be determined (explain): ________________________+ MGMT Promoter Methylation+ ___ Present If laboratory reports by level:+ ___ Low level + ___ High level+ ___ Absent+ ___ Cannot be determined (explain): ________________________+ BRAF Mutation+ ___ BRAF V600E (c.1799T>A) mutation present+ ___ Other BRAF mutation present (specify): ________________________+ ___ Absent + ___ Cannot be determined (explain): ________________________+ BRAF V600E Immunohistochemistry+ ___ Positive+ ___ Negative + ___ Cannot be determined (explain): ________________________+ BRAF Rearrangement+ ___ Present+ ___ Absent+ ___ Cannot be determined (explain): ________________________+ Ki-67+ Percentage of positive nuclei: ____ %+ EMBRYONAL TUMORS+ Nuclear Beta-Catenin Immunohistochemistry + ___ Positive (nuclear staining in at least 50% of tumor cells)+ ___ Negative (no staining or nuclear staining in <50% of tumor cells)+ ___ Cannot be determined (explain): ________________________+ Monosomy 6+ ___ Present+ ___ Absent+ ___ Cannot be determined (explain): ________________________+ GAB1 Immunohistochemistry+ ___ Positive+ ___ Negative + ___ Cannot be determined (explain): ________________________+ MYC Amplification+ ___ Present+ ___ Absent+ ___ Cannot be determined (explain): ________________________+ MYCN Amplification+ ___ Present+ ___ Absent+ ___ Cannot be determined (explain): ________________________+ Isochromosome 17 (i17q)+ ___ Present+ ___ Absent + ___ Cannot be determined (explain): ________________________+ INI1 (BAF47) Immunohistochemistry+ ___ Loss of nuclear expression + ___ Intact nuclear expression+ ___ Cannot be determined (explain): ________________________+ SMARCB1/INI1/HNSF5 Mutation+ ___ Present (specify): ________________________+ ___ Absent (SMARCB1/INI1/HNSF5)+ ___ Cannot be determined (explain): ________________________+ METHODS+ GLIOMAS+ IDH1/2 Mutational Analysis+ Testing Method (select all that apply)+ ___ Direct Sanger sequencing+ ___ Pyrosequencing+ ___ Polymerase chain reaction (PCR), allele-specific hybridization+ ___ Real-time PCR+ ___ High-throughput next-generation sequencing+ ___ Other (specify): ______________________+ Immunohistochemistry for IDH1 R132H+ Primary Antibody+ ___ H09+ ___ Other (specify): ________________________+ 1p/19q Deletion Analysis+ Testing Method (select all that apply)+ ___ In situ hybridization+ ___ Cytogenomic microarray (CMA)+ ___ Loss of heterozygosity+ ___ Other (specify): __________________________+ TP53 Mutational?Analysis+ Testing Method (select all that apply)+ ___ Direct Sanger sequencing+ ___ Pyrosequencing+ ___ PCR, allele-specific hybridization+ ___ Real-time PCR+ ___ High-throughput next-generation sequencing+ ___ Other (specify): ________________________+ ATRX Mutational?Analysis+ Testing Method (select all that apply)+ ___ Direct Sanger sequencing+ ___ Pyrosequencing+ ___ PCR, allele-specific hybridization+ ___ Real-time PCR+ ___ High-throughput next-generation sequencing+ ___ Other (specify): ________________________+ Immunohistochemistry for ATRX+ Primary Antibody+ Specify: ________________________ + EGFR Amplification Analysis + Testing Method (select all that apply)+ ___ In situ hybridization+ ___ Cytogenomic microarray (CMA)+ ___ Other (specify): ________________________+ Chromosome 10q23 (PTEN Locus) Deletion Analysis+ Testing Method (select all that apply)+ ___ In situ hybridization+ ___ Cytogenomic microarray (CMA)+ ___ Loss of heterozygosity+ ___ Other (specify): ________________________+ PTEN Mutational?Analysis+ Testing Method (select all that apply)+ ___ Direct Sanger sequencing+ ___ Pyrosequencing+ ___ PCR, allele-specific hybridization+ ___ Real-time PCR+ ___ High-throughput next-generation sequencing+ ___ Other (specify): ________________________+ MGMT Promoter Methylation+ Testing Method (select all that apply)+ ___ Methylation-specific PCR+ ___ Other (specify): ________________________+ BRAF V600E Mutational Analysis+ Mutations Assessed (select all that apply)+ ___ V600E+ ___ Any mutation in exon 15+ ___ Other (specify): ________________________+ Testing Method (select all that apply)+ ___ Direct Sanger sequencing+ ___ Pyrosequencing+ ___ PCR, allele-specific hybridization+ ___ Real-time PCR+ ___ High-throughput next-generation sequencing+ ___ Other (specify): ________________________+ Immunohistochemistry for BRAF V600E + Primary Antibody+ ___ VE1+ ___ Other (specify): ________________________+ BRAF Rearrangement Analysis+ Testing Method (select all that apply)+ ___ In situ hybridization+ ___ Cytogenomic microarray (CMA)+ ___ Real-time PCR+ ___ Other (specify): ________________________+ Immunohistochemistry for Ki-67+ Primary Antibody+ ___ MIB1+ ___ SP6+ ___ Other (specify): ________________________+ EMBRYONAL TUMORS+ Immunohistochemistry for Beta-Catenin+ Primary Antibody+ ___ E-5+ ___ 14+ ___ Beta-catenin-1+ ___ Other (specify): ________________________+ Monosomy 6 Analysis+ Testing Method (select all that apply)+ ___ In situ hybridization+ ___ Cytogenomic microarray (CMA)+ ___ Other (specify): ________________________+ Immunohistochemistry for GAB1 + Primary Antibody+ Specify: ________________________ + MYC Amplification Analysis+ Testing Method (select all that apply)+ ___ In situ hybridization+ ___ Cytogenomic microarray (CMA)+ ___ Other (specify): ________________________+ MYCN Amplification Analysis + Testing Method (select all that apply)+ ___ In situ hybridization+ ___ Cytogenomic microarray (CMA)+ ___ Other (specify): ________________________+ Isochromosome 17 (i17q) Analysis+ Testing Method (select all that apply)+ ___ In situ hybridization+ ___ Cytogenomic microarray (CMA)+ ___ Other (specify): ________________________+ Immunohistochemistry for INI1 (BAF47)+ Primary Antibody+ ___ MRQ-27+ ___ 25/BAF47+ ___ Other (specify): ________________________+ SMARCB1/INI1/HNSF5 Mutational Analysis+ Testing Method (select all that apply)+ ___ Direct Sanger sequencing+ ___ Pyrosequencing+ ___ PCR, allele-specific hybridization+ ___ Real-time PCR+ ___ High-throughput next-generation sequencing+ ___ Other (specify): ______________________+ Comments: __________________________________________ __________________________________________Explanatory NotesThe diagnosis of central nervous system (CNS) tumors increasingly relies on molecular genetic applications to aid in classification, offer prognostic value, and predict response to therapy.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWtpZm9yb3ZhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh
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ADDIN EN.CITE.DATA 1-6 These applications may assess genetic losses, amplifications, translocations, mutations, or the expression levels of specific gene transcripts or proteins. Molecular diagnostics is quickly transitioning from testing for one biomarker at a time to a panel-based approach and whole genome analysis. Frequently employed methods for genetic testing are gene sequencing, fluorescence in situ hybridization (FISH), and cytogenomic microarray (CMA). In some cases, immunohistochemistry can be used as a surrogate for genetic analysis when the marker gene is consistently overexpressed or underexpressed. This template for reporting results of biomarker testing for CNS tumors represents a common framework for the reporting of molecular findings relevant to these diseases and does not advocate their specific application. GLIOMASIsocitrate Dehydrogenase (IDH)Isocitrate dehydrogenase (IDH) is an enzyme that exists in 5 isoforms, each of which catalyzes the reaction of isocitrate to α-ketoglutarate.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJzb25zPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48
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AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==
ADDIN EN.CITE.DATA 8 Mutations in IDH2 have also been detected in these same tumor types, but much less frequently. IDH mutations are infrequent in de novo GBMs. The mutant forms of IDH1 and IDH2 lead to the production of the oncometabolite 2-hydroxyglutarate, which inhibits the function of numerous α-ketoglutarate–dependent enzymes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdXJjYW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdXJjYW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA=
ADDIN EN.CITE.DATA 9 Inhibition of the family of histone demethylases and the TET family of 5-methylcytosine hydroxylases has profound effect on the epigenetic status of mutated cells and leads directly to a hypermethylator phenotype that has been referred to as the CpG island methylator phenotype (G-CIMP).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3VzaG1laHI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy
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ADDIN EN.CITE.DATA 10 The finding of IDH mutations in an infiltrating glioma is associated with substantially improved prognosis, grade for grade. Indeed, IDH mutant GBMs, WHO grade IV, are associated with longer survivals than IDH wild-type anaplastic astrocytomas, WHO grade III. Over 90% of IDH1 mutations in diffuse gliomas occur at a specific site and are characterized by a base exchange of guanine to adenine within codon 132, resulting in an amino acid change from arginine to histidine (R132H). Because of this consistent protein alteration, a monoclonal antibody has been developed to the mutant protein, allowing its use in paraffin-embedded specimens (mIDH1R132H).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXBwZXI8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 11 The ability of the antibody to detect a small number of cells as mutant may make this method more sensitive than sequencing for identifying R132H mutant gliomas. However, mutations in IDH2 and other mutations in IDH1 will not be detected using immunohistochemistry with this antibody.1p/19qOne of the best studied relationships between genetic alterations and glioma histology is the strong association of allelic losses on chromosomes 1p and 19q and the oligodendroglioma phenotype.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWlybmNyb3NzPC9BdXRob3I+PFllYXI+MTk5ODwvWWVh
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ADDIN EN.CITE.DATA 12,13 Approximately 60% to 80% of oligodendroglial neoplasms demonstrate combined 1p and 19q losses, and those oligodendrogliomas that are morphologically classic have even higher frequencies.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJnZXI8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxS
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJnZXI8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 14 Most studies have indicated that combined losses of 1p and 19q are specific to oligodendrogliomas, with only few astrocytomas and a small subset of oligoastrocytomas harboring these alterations. Those oligodendrogliomas with 1p/19q loss show enhanced response to chemotherapy and are associated with prolonged survival. Co-deletion of 1p/19q occurs by an unbalanced translocation after which only one copy of the short arm of chromosome 1 and one copy of the long arm of chromosome 19 remain and der(1;19) (q10;p10) is produced.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KZW5raW5zPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48
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ADDIN EN.CITE.DATA 18 Oligodendrogliomas of grades II and III that have 1p/19q co-deletion also have a high frequency of TERT promoter mutations, CIC mutations on the remaining chromosome 1p allele and FUBP1 mutation on the remaining 19q allele.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWxsZWxhPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 8,20,21 The vast majority of diffuse astrocytomas that have IDH mutations also harbor a TP53 mutation. ADDIN EN.CITE <EndNote><Cite><Author>Liu</Author><Year>2012</Year><RecNum>8419</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>8419</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">8419</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liu, X. Y.</author><author>Gerges, N.</author><author>Korshunov, A.</author><author>Sabha, N.</author><author>Khuong-Quang, D. A.</author><author>Fontebasso, A. M.</author><author>Fleming, A.</author><author>Hadjadj, D.</author><author>Schwartzentruber, J.</author><author>Majewski, J.</author><author>Dong, Z.</author><author>Siegel, P.</author><author>Albrecht, S.</author><author>Croul, S.</author><author>Jones, D. T.</author><author>Kool, M.</author><author>Tonjes, M.</author><author>Reifenberger, G.</author><author>Faury, D.</author><author>Zadeh, G.</author><author>Pfister, S.</author><author>Jabado, N.</author></authors></contributors><auth-address>Department of Human Genetics, McGill University, Montreal, QC, Canada.</auth-address><titles><title>Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations</title><secondary-title>Acta Neuropathol</secondary-title></titles><periodical><full-title>Acta Neuropathol</full-title></periodical><pages>615-25</pages><volume>124</volume><number>5</number><edition>2012/08/14</edition><dates><year>2012</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1432-0533 (Electronic)
0001-6322 (Linking)</isbn><accession-num>22886134</accession-num><urls><related-urls><url> In one study, 80% of anaplastic astrocytomas and GBMs that had an IDH1 or IDH2 mutation also carried a TP53 mutation. Conversely, TP53 mutations were identified in only 18% of high-grade astrocytomas that lacked an IDH1 or IDH2 mutation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 8 Thus, there is a strong association between IDH1 mutation and TP53 mutation in diffuse astrocytomas, and this combination of mutations is helpful in distinguishing astrocytomas from oligodendroglimas. Immunohistochemical reactivity for the p53 protein is often used as a marker for astrocytic differentiation in diffuse gliomas, since the mutant protein is degraded more slowly and accumulates in the nucleus of tumor cells. This immunostain reacts with both the normal and mutant forms of p53 and therefore is not entirely specific for TP53 mutations.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdXJ0a2F5YS1ZYXBpY2llcjwvQXV0aG9yPjxZZWFyPjIw
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ADDIN EN.CITE.DATA 23ATRXIDH1 mutation and TP53 mutation in infiltrating gliomas are strongly associated with inactivating alterations in Alpha Thalassemia/Mental Retardation Syndrome X-linked (ATRX), a gene that encodes a protein involved in chromatin remodeling.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 22,24 ATRX mutations are a marker of astrocytic lineage among the IDH mutant gliomas and are mutually exclusive with 1p/19q codeletion. Mutations are most frequent in grade II (67%) and grade III (73%) astrocytomas and secondary GBMs (57%), while they are uncommon in primary GBMs and oligodendrogliomas. Nearly all diffuse gliomas with IDH and ATRX mutations also harbor TP53 mutation and are associated with the alternative lengthening of telomeres (ALT) phenotype.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KaWFvPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 24 Immunohistochemistry for ATRX demonstrates a loss of protein expression in neoplastic cells that harbor inactivating mutations, while expression is retained in nonneoplastic cells within the sample (eg, endothelial cells).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWVzdGxlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
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ADDIN EN.CITE.DATA 27 EGFR amplification is much more frequent in de novo (primary) GBMs than in secondary GBMs. ADDIN EN.CITE <EndNote><Cite><Author>Ohgaki</Author><Year>2007</Year><RecNum>8527</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>8527</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">8527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ohgaki, H.</author><author>Kleihues, P.</author></authors></contributors><auth-address>International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France. ohgaki@iarc.fr</auth-address><titles><title>Genetic pathways to primary and secondary glioblastoma</title><secondary-title>Am J Pathol</secondary-title></titles><periodical><full-title>Am J Pathol</full-title></periodical><pages>1445-53</pages><volume>170</volume><number>5</number><edition>2007/04/26</edition><keywords><keyword>Brain Neoplasms/*genetics/*pathology</keyword><keyword>Chromosomes, Human, Pair 10/genetics</keyword><keyword>Glioblastoma/*genetics/*pathology</keyword><keyword>Humans</keyword><keyword>Loss of Heterozygosity/genetics</keyword><keyword>Mutation</keyword><keyword>PTEN Phosphohydrolase/genetics</keyword><keyword>Tumor Suppressor Protein p53/genetics</keyword></keywords><dates><year>2007</year><pub-dates><date>May</date></pub-dates></dates><isbn>0002-9440 (Print)
0002-9440 (Linking)</isbn><accession-num>17456751</accession-num><urls><related-urls><url>(10)61358-2 [pii]
10.2353/ajpath.2007.070011</electronic-resource-num><language>eng</language></record></Cite></EndNote>28 Approximately one-half of those GBMs with EGFR amplification also have specific EGFR mutations (the vIII mutant), which produce a truncated transmembrane receptor with constitutive activity. Both EGFR amplification and the EGFRvIII mutant are mutually exclusive with IDH mutations. EGFR amplification is specific to those gliomas that are astrocytic in differentiation and of higher grade, such as anaplastic astrocytoma, WHO grade III, and GBM, WHO grade IV.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 29 This molecular finding can be useful in distinguishing the morphologically similar small cell GBM, which harbor the amplification, from anaplastic oligodendrogliomas, which does not. ADDIN EN.CITE <EndNote><Cite><Author>Perry</Author><Year>2004</Year><RecNum>96</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>96</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">96</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Perry, A.</author><author>Aldape, K. D.</author><author>George, D. H.</author><author>Burger, P. C.</author></authors></contributors><auth-address>Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA. aperry@wustl.edu</auth-address><titles><title>Small cell astrocytoma: an aggressive variant that is clinicopathologically and genetically distinct from anaplastic oligodendroglioma</title><secondary-title>Cancer</secondary-title></titles><periodical><full-title>Cancer</full-title></periodical><pages>2318-26</pages><volume>101</volume><number>10</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Astrocytoma/*genetics/*pathology</keyword><keyword>Brain Neoplasms/*genetics/pathology</keyword><keyword>Carcinoma, Small Cell/*genetics/*pathology</keyword><keyword>Diagnosis, Differential</keyword><keyword>Female</keyword><keyword>Gene Dosage</keyword><keyword>Humans</keyword><keyword>In Situ Hybridization, Fluorescence</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Oligodendroglioma/*genetics/pathology</keyword><keyword>Receptor, Epidermal Growth Factor/genetics/metabolism</keyword><keyword>Research Support, U.S. Gov't, P.H.S.</keyword></keywords><dates><year>2004</year><pub-dates><date>Nov 15</date></pub-dates></dates><accession-num>15470710</accession-num><urls><related-urls><url> PTEN and LOH Chromosome 10Loss of the entire chromosome (monosomy), deletions, and copy neutral loss of heterozygosity (LOH) of chromosome 10 occurs in 60% to 95% of GBMs and less frequently in grade II or III diffuse astrocytomas. ADDIN EN.CITE <EndNote><Cite><Author>Ohgaki</Author><Year>2007</Year><RecNum>8527</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>8527</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">8527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ohgaki, H.</author><author>Kleihues, P.</author></authors></contributors><auth-address>International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France. ohgaki@iarc.fr</auth-address><titles><title>Genetic pathways to primary and secondary glioblastoma</title><secondary-title>Am J Pathol</secondary-title></titles><periodical><full-title>Am J Pathol</full-title></periodical><pages>1445-53</pages><volume>170</volume><number>5</number><edition>2007/04/26</edition><keywords><keyword>Brain Neoplasms/*genetics/*pathology</keyword><keyword>Chromosomes, Human, Pair 10/genetics</keyword><keyword>Glioblastoma/*genetics/*pathology</keyword><keyword>Humans</keyword><keyword>Loss of Heterozygosity/genetics</keyword><keyword>Mutation</keyword><keyword>PTEN Phosphohydrolase/genetics</keyword><keyword>Tumor Suppressor Protein p53/genetics</keyword></keywords><dates><year>2007</year><pub-dates><date>May</date></pub-dates></dates><isbn>0002-9440 (Print)
0002-9440 (Linking)</isbn><accession-num>17456751</accession-num><urls><related-urls><url>(10)61358-2 [pii]
10.2353/ajpath.2007.070011</electronic-resource-num><language>eng</language></record></Cite></EndNote>28 Loss of large regions at 10p, 10q23 and 10q25-26 loci, or loss of an entire copy of chromosome 10 are the most frequent genetic alterations in GBMs. ADDIN EN.CITE <EndNote><Cite><Author>Nikiforova</Author><Year>2011</Year><RecNum>8542</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>8542</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">8542</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nikiforova, M. N.</author><author>Hamilton, R. L.</author></authors></contributors><auth-address>Department of Pathology, University of Pittsburgh, 200 Lothrop Ave, Pittsburgh, PA 15213, USA. nikiforovamn@upmc.edu</auth-address><titles><title>Molecular diagnostics of gliomas</title><secondary-title>Arch Pathol Lab Med</secondary-title></titles><periodical><full-title>Arch Pathol Lab Med</full-title></periodical><pages>558-68</pages><volume>135</volume><number>5</number><edition>2011/04/30</edition><keywords><keyword>Brain Neoplasms/*diagnosis/genetics</keyword><keyword>Chromosome Deletion</keyword><keyword>Chromosomes, Human, Pair 1</keyword><keyword>Chromosomes, Human, Pair 19</keyword><keyword>Glioma/*diagnosis/genetics</keyword><keyword>Humans</keyword><keyword>Molecular Diagnostic Techniques/*methods</keyword><keyword>Mutation</keyword><keyword>Prognosis</keyword><keyword>Tumor Markers, Biological/genetics</keyword></keywords><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1543-2165 (Electronic)
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ADDIN EN.CITE.DATA 4,31 The clinical significance of polysomy involving chromosome 10 is not fully understood.MGMTThe current standard therapy for GBM includes radiation and chemotherapy with temozolomide, which acts by crosslinking DNA by alkylating multiple sites including the O6 position of guanine.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHVwcDwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 32 DNA crosslinking at the O6 position of guanine is reversed by the DNA repair enzyme MGMT (O6-methylguanine-DNA methyltransferase). Thus, low levels of MGMT expression by GBM cells would be expected to be associated with an enhanced response to alkylating agents. The expression level of MGMT is determined in large part by the methylation status of the gene’s promoter. This “epigenetic silencing” of MGMT occurs in 40% to 50% of GBMs and can be assessed by its promoter methylation status on PCR-based tests of genomic DNA. Some laboratories report the promoter methylation status as “low level” and “high level,” or indicate that “partial methylation” is present, yet the clinical implications of this distinction are not fully understood. Most investigations have shown that epigenetic gene silencing of MGMT is a strong predictor of prolonged survival, independent of other clinical factors or treatment.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWdpPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 33, 34BRAFGenomic alterations involving BRAF are common in sporadic cases of pilocytic astrocytoma and result in the downstream activation of the ERK/MAPK pathway. ADDIN EN.CITE <EndNote><Cite><Author>Rodriguez</Author><Year>2013</Year><RecNum>8546</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>8546</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">8546</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rodriguez, F. J.</author><author>Lim, K. S.</author><author>Bowers, D.</author><author>Eberhart, C. G.</author></authors></contributors><auth-address>Department of Pathology, Johns Hopkins UniversitySchool of Medicine, Baltimore, Maryland 21205, USA.</auth-address><titles><title>Pathological and molecular advances in pediatric low-grade astrocytoma</title><secondary-title>Annu Rev Pathol</secondary-title></titles><periodical><full-title>Annu Rev Pathol</full-title></periodical><pages>361-79</pages><volume>8</volume><edition>2012/11/06</edition><keywords><keyword>Animals</keyword><keyword>Astrocytoma/genetics/metabolism/*pathology</keyword><keyword>Brain Neoplasms/genetics/metabolism/*pathology/therapy</keyword><keyword>Humans</keyword><keyword>Neoplasm Grading</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan 24</date></pub-dates></dates><isbn>1553-4014 (Electronic)
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ADDIN EN.CITE.DATA 35 This fusion is seen in the majority of cerebellar and midline pilocytic astrocytomas, but is present at lower frequency in cerebral tumors. ADDIN EN.CITE <EndNote><Cite><Author>Horbinski</Author><Year>2013</Year><RecNum>8470</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>8470</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">8470</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Horbinski, C.</author></authors></contributors><auth-address>Department of Pathology, University of Kentucky, Lexington, Kentucky 40536, USA. craig.horbinski@uky.edu</auth-address><titles><title>To BRAF or not to BRAF: is that even a question anymore?</title><secondary-title>J Neuropathol Exp Neurol</secondary-title></titles><periodical><full-title>J Neuropathol Exp Neurol</full-title></periodical><pages>2-7</pages><volume>72</volume><number>1</number><edition>2012/12/18</edition><keywords><keyword>Animals</keyword><keyword>Brain Neoplasms/diagnosis/*genetics</keyword><keyword>Child</keyword><keyword>Glioma/diagnosis/*genetics</keyword><keyword>Humans</keyword><keyword>Point Mutation/*genetics</keyword><keyword>Proto-Oncogene Proteins B-raf/*genetics</keyword><keyword>Signal Transduction/genetics</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1554-6578 (Electronic)
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ADDIN EN.CITE.DATA 37 While these tumor types are most frequently encountered in children, they are also occasionally seen in adults and have similar BRAF mutations. Although less common, diffusely infiltrative gliomas including GBM, particularly the epithelioid variant, may also demonstrate the V600E mutation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGk8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 27,38-40 More recently, BRAF mutations have been identified in papillary craniopharyngiomas. ADDIN EN.CITE <EndNote><Cite><Author>Larkin</Author><Year>2014</Year><RecNum>8719</RecNum><DisplayText><style face="superscript">41</style></DisplayText><record><rec-number>8719</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">8719</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Larkin, S. J.</author><author>Preda, V.</author><author>Karavitaki, N.</author><author>Grossman, A.</author><author>Ansorge, O.</author></authors></contributors><auth-address>Nuffield Department of Clinical Neurosciences, Department of Neuropathology, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK.</auth-address><titles><title>BRAF V600E mutations are characteristic for papillary craniopharyngioma and may coexist with CTNNB1-mutated adamantinomatous craniopharyngioma</title><secondary-title>Acta Neuropathol</secondary-title></titles><periodical><full-title>Acta Neuropathol</full-title></periodical><edition>2014/04/10</edition><dates><year>2014</year><pub-dates><date>Apr 9</date></pub-dates></dates><isbn>1432-0533 (Electronic)
0001-6322 (Linking)</isbn><accession-num>24715106</accession-num><urls><related-urls><url> most reliable and technically feasible marker of proliferation for gliomas is Ki-67, a nuclear antigen expressed in cells actively engaged in the cell cycle but not expressed in the resting phase, G0. ADDIN EN.CITE <EndNote><Cite><Author>Brat</Author><Year>2008</Year><RecNum>411</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>411</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">411</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brat, D. J.</author><author>Prayson, R. A.</author><author>Ryken, T. C.</author><author>Olson, J. J.</author></authors></contributors><auth-address>Department of Pathology and Laboratory Medicine, Emory University Hospital, G-169, 1364 Clifton Rd. NE, Atlanta, GA 30322, USA. dbrat@emory.edu</auth-address><titles><title>Diagnosis of malignant glioma: role of neuropathology</title><secondary-title>J Neurooncol</secondary-title></titles><periodical><full-title>J Neurooncol</full-title></periodical><pages>287-311</pages><volume>89</volume><number>3</number><keywords><keyword>Brain Neoplasms/*classification/*diagnosis/genetics</keyword><keyword>Genetic Techniques</keyword><keyword>Glioma/*classification/*diagnosis/genetics</keyword><keyword>Histological Techniques</keyword><keyword>Humans</keyword></keywords><dates><year>2008</year><pub-dates><date>Sep</date></pub-dates></dates><accession-num>18712282</accession-num><urls><related-urls><url> Results are expressed as a percentage of positive staining tumor cell nuclei (Ki-67 labeling index). Numerous investigations have demonstrated a positive correlation between Ki-67 indices and histologic grade for astrocytomas, oligodendrogliomas, and oligoastrocytomas.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaWFubmluaTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA 42 In contrast, investigations of Ki-67 proliferation on patient outcome for GBM, WHO grade IV, have consistently concluded that it does not provide prognostic value in this set of tumors. ADDIN EN.CITE <EndNote><Cite><Author>Moskowitz</Author><Year>2006</Year><RecNum>84</RecNum><DisplayText><style face="superscript">44</style></DisplayText><record><rec-number>84</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">84</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Moskowitz, S. I.</author><author>Jin, T.</author><author>Prayson, R. A.</author></authors></contributors><auth-address>Department of Neurosurgery, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.</auth-address><titles><title>Role of MIB1 in predicting survival in patients with glioblastomas</title><secondary-title>J Neurooncol</secondary-title></titles><periodical><full-title>J Neurooncol</full-title></periodical><pages>193-200</pages><volume>76</volume><number>2</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Neoplasms/*metabolism/radiotherapy/surgery</keyword><keyword>Combined Modality Therapy</keyword><keyword>Female</keyword><keyword>Glioblastoma/*metabolism/radiotherapy/surgery</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Karnofsky Performance Status</keyword><keyword>Ki-67 Antigen/*metabolism</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Retrospective Studies</keyword><keyword>Survival Analysis</keyword><keyword>Tumor Markers, Biological/*metabolism</keyword></keywords><dates><year>2006</year><pub-dates><date>Jan</date></pub-dates></dates><accession-num>16234986</accession-num><urls><related-urls><url> One potential shortcoming of Ki-67 as a marker is the high degree of variability in tissue processing, immunohistochemical staining, and quantization techniques between laboratories, making it difficult to standardize proliferation indices. ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>2001</Year><RecNum>68</RecNum><DisplayText><style face="superscript">45</style></DisplayText><record><rec-number>68</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">68</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marie, D.</author><author>Liu, Y.</author><author>Moore, S. A.</author><author>Brown, H. G.</author><author>Silverman, J. F.</author><author>D'Amico, F.</author><author>Raab, S. S.</author></authors></contributors><auth-address>Department of Pathology and Laboratory Medicine, Allegheny General Hospital and MCP Hahnemann University, Pittsburgh, Pennsylvania 15212, USA. dgrzybic@</auth-address><titles><title>Interobserver variability associated with the MIB-1 labeling index: high levels suggest limited prognostic usefulness for patients with primary brain tumors</title><secondary-title>Cancer</secondary-title></titles><periodical><full-title>Cancer</full-title></periodical><pages>2720-6</pages><volume>92</volume><number>10</number><keywords><keyword>Antigens, Nuclear</keyword><keyword>Brain Neoplasms/*pathology</keyword><keyword>Glioma/*pathology</keyword><keyword>Humans</keyword><keyword>Ki-67 Antigen</keyword><keyword>Nuclear Proteins/*analysis</keyword><keyword>Observer Variation</keyword><keyword>Prognosis</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Tumor Markers, Biological/*analysis</keyword></keywords><dates><year>2001</year><pub-dates><date>Nov 15</date></pub-dates></dates><accession-num>11745208</accession-num><urls><related-urls><url> Large variations in proliferation rates within a single tumor may also be noted. Nonetheless, when interpreted uniformly within a given laboratory, the Ki-67 proliferation index provides prognostic value to clinicians and can be helpful in histologically borderline cases, such as those that are at the grade II to III and III to IV border. A high labeling index in this setting may indicate a more aggressive neoplasm. EMBRYONAL TUMORS Medulloblastoma MarkersMedulloblastomas are primitive embryonal neoplasms of the cerebellum, generally arising in childhood, whose molecular genetic alterations have now been well defined. Four subgroups have been described based on gene expression profiles: wingless (WNT), sonic hedgehog (SHH), "group 3," and "group 4."PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3J0aGNvdHQ8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy
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AG==
ADDIN EN.CITE.DATA 47 Medulloblastomas with >50% nuclear staining for beta-catenin have been shown to have WNT pathway activation, CTNNB1 mutations, and monosomy 6, whereas those with only focal nuclear staining do not.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GYXR0ZXQ8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 48 The overall survivals for WNT pathway medulloblastomas are dramatically longer than those of the other subtypes, and clinical practices are changing in light of this.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZmlzdGVyPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZmlzdGVyPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA 49 SHH medulloblastomas often show a nodular/desmoplastic histology and are associated with a better prognosis in younger children and infants. 9q deletion is characteristic of the SHH group, and MYCN amplifications are occasionally noted. GAB1 is expressed in the cytoplasm of nearly all SHH medulloblastomas but not in other groups and can be detected immunohistochemically, making it a valuable SHH-group marker.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGxpc29uPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGxpc29uPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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AG==
ADDIN EN.CITE.DATA 47 Targeted therapies directed at this subgroup have been established and are entering clinical practice.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdWRpbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 49 Approximately 30% to 40% of all medulloblastomas have i(17q), making it the most common genetic defect. Those tumors with i(17q) have a worse prognosis than those that don’t. Among the genetic markers for medulloblastoma, monosomy 6 (or nuclear beta-catenin immunoreactivity), GAB1 expression, MYC or MYCN amplification, and i(17q) appear to be the most reliable and carry the strongest prognostic and therapeutic implications. INI1The atypical teratoid/rhabdoid tumor (AT/RT) is a clinically aggressive embryonal tumor of infancy that occurs in the posterior fossa and cerebral hemispheres. ADDIN EN.CITE <EndNote><Cite><Author>Louis</Author><Year>2007</Year><RecNum>182</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>182</rec-number><foreign-keys><key app="EN" db-id="d00w0dwd9ez9x3edw0ap00wwr5a5za2tprsp">182</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Louis, D.N.,Ohgaki, H., Wiestler, O.D., Cavenee, W.K.</author></authors></contributors><titles><title>WHO Classification of Tumours of the Central Nervous System.</title></titles><pages>309</pages><edition>4th</edition><dates><year>2007</year></dates><pub-location>Lyon</pub-location><publisher>Intl. Agency for Research</publisher><urls></urls></record></Cite></EndNote>6 The tumor is characterized by deletions and mutations of SMARCB1/INI1 (HSNF5) (22q11.2).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWVnZWw8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 52,53 Immunohistochemical evaluation of AT/RT for the INI1 protein (using the BAF47 antibody) shows a loss of labeling in tumor cell nuclei, but retention of nuclear labeling in nonneoplastic cells, such as endothelial cells. The recognition of AT/RT is important for clinical management, since AT/RTs have morphologic overlap with medulloblastoma, CNS primitive neuroectodermal tumor (PNET), choroid plexus carcinoma, GBM, and other malignant tumors of childhood.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KdWRraW5zPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
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ADDIN EN.CITE.DATA 54 The diagnosis of AT/RT and the finding of SMARCB1/INI1 loss or mutation also carry potential implications for inheritance. These tumors are often a component of the rhabdoid tumor predisposition syndrome (RTPS), characterized by germline mutations of SMARCB1/INI1 and manifested by a marked predisposition to the development of malignant rhabdoid tumors of infancy and early childhood.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWVnZWw8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS
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