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1. Clinical characteristics and clinical evolution of a large cohort of pediatric patients with primary central nervous system (cns) tumors and tropomyosin receptor kinase (trk) fusion.

Author

Lamoureux A.-A., Fisher M., Lemelle L., Pfaff E., Kramm C., De Wilde B., Kazanowska B., Hutter C., Pfister S.M., Sturm D., Jones D., Orbach D., Pierron G., Raskin S., Drilon A., Diamond E., Harada G., Zapotocky M., Ellezam B., Weil A.G., Venne D., Barritault M., Leblond P., Coltin H., Hammad R., Tabori U., Hawkins C., Hansford J.R., Meyran D., Erker C., McFadden K., Sato M., Gottardo N.G., Dholaria H., Noroxe D.S., Goto H., Ziegler D.S., Lin F.Y., Parsons D.W., Lindsay H., Wong T.-T., Liu Y.-L., Wu K.-S., Franson A.F., Hwang E., Aguilar-Bonilla A., Cheng S., Cacciotti C., Massimino M., Schiavello E., Wood P., Hoffman L.M., Cappellano A., Lassaletta A., Van Damme A., Llort A., Gerber N.U., Ceruso M.S., Bendel A.E., Skrypek M., Hamideh D., Mushtaq N., Walter A., Jabado N., Alsahlawi A., Farmer J.-P., Abadi C.C., Mueller S., Mazewski C., Aguilera D., Robison N., O'Halloran K., Abbou S., Berlanga P., Geoerger B., Ora I., Moertel C.L., Razis E.D., Vernadou A., Doz F., Laetsch T.W., Perreault S., Lamoureux A.-A., Fisher M., Lemelle L., Pfaff E., Kramm C., De Wilde B., Kazanowska B., Hutter C., Pfister S.M., Sturm D., Jones D., Orbach D., Pierron G., Raskin S., Drilon A., Diamond E., Harada G., Zapotocky M., Ellezam B., Weil A.G., Venne D., Barritault M., Leblond P., Coltin H., Hammad R., Tabori U., Hawkins C., Hansford J.R., Meyran D., Erker C., McFadden K., Sato M., Gottardo N.G., Dholaria H., Noroxe D.S., Goto H., Ziegler D.S., Lin F.Y., Parsons D.W., Lindsay H., Wong T.-T., Liu Y.-L., Wu K.-S., Franson A.F., Hwang E., Aguilar-Bonilla A., Cheng S., Cacciotti C., Massimino M., Schiavello E., Wood P., Hoffman L.M., Cappellano A., Lassaletta A., Van Damme A., Llort A., Gerber N.U., Ceruso M.S., Bendel A.E., Skrypek M., Hamideh D., Mushtaq N., Walter A., Jabado N., Alsahlawi A., Farmer J.-P., Abadi C.C., Mueller S., Mazewski C., Aguilera D., Robison N., O'Halloran K., Abbou S., Berlanga P., Geoerger B., Ora I., Moertel C.L., Razis E.D., Vernadou A., Doz F., Laetsch T.W., and Perreault S.

Abstract

BACKGROUND: TRK fusions are detected in less than 3% of CNS tumors. Given their rarity, there are limited data on the clinical course of these patients. METHOD(S): We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, NTRK gene fusion, treatment modalities and outcomes. Patients less than 18 years of age at diagnosis were included in this analysis. RESULT(S): Seventy-three pediatric patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 2.4 years (range 0.0-17.8) and 60.2 % were male. NTRK2 gene fusions were found in 37 patients (50.7%), NTRK1 and NTRK3 aberrations were detected in 19 (26.0%) and 17 (23.3%), respectively. Tumor types included 38 high-grade gliomas (HGG; 52.1%), 20 low-grade gliomas (LGG; 27.4%), 4 embryonal tumors (5.5%) and 11 others (15.1%). Median follow-up was 46.5 months (range 3-226). During the course of their disease, a total of 62 (84.9%) patients underwent surgery with a treatment intent, 50 (68.5%) patients received chemotherapy, 35 (47.9%) patients received radiation therapy, while 34 (46.6%) patients received NTRK inhibitors (3 as first line treatment). Twenty-four (32.9%) had no progression including 9 LGG (45%) and 9 HGG (23.6%). At last follow-up, only one (5.6%-18 evaluable) patient with LGG died compared to 11 with HGG (35.5%-31 evaluable). For LGG the median progression-free survival (PFS) after the first line of treatment was 17 months (95% CI: 0.0-35.5) and median overall survival (OS) was not reached. For patients with HGG the median PFS was 30 months (95% CI: 11.9-48.1) and median OS was 182 months (95% CI 20.2-343.8). CONCLUSION(S): We report the largest cohort of pediatric patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.

Published
2022

2. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number

Author

Parsons, D.W., McAndrew, P.E., Iannaccone, S.T., Mendell, J.R., Burghes, A.H.M., and Prior, T.W.

Subjects
Chromosome mapping -- Usage, Genetic disorders -- Research, Spinal muscular atrophy -- Genetic aspects, Biological sciences
Abstract

Modification of the spinal muscular atrophy phenotype by centromeric survival motor neuron (cenSMN) copy number is discussed with information on the distribution, frequency and evidence of a founder effect. Intragenic telomeric survival motor neuron (telSMN) mutations so far identified cluster at the 3' end of the survival motor neuron gene, while the novel A2G missense mutation occurs outside the conserved carboxy-terminal domain, and in 3 of 23 patients the A2G mutation was on the same allele as a rare polymorphism in the 5' UTR.

Published
1998

3. Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Author

Stankiewicz, P., Khan, T.N., Szafranski, P., Slattery, L., Streff, H., Vetrini, F., Bernstein, J.A., Brown, C.W., Rosenfeld, J.A., Rednam, S., Scollon, S., Bergstrom, K.L., Parsons, D.W., Plon, S.E., Vieira, M.W., Quaio, C., Baratela, W.A.R., Guio, J.C.A., Armstrong, R., Mehta, S.G., Rump, P., Pfundt, R.P., Lewandowski, R., Fernandes, E.M., Shinde, D.N., Tang, S., Hoyer, J., Zweier, C., Reis, A., Bacino, C.A., Xiao, R., Breman, A.M., Smith, J.L., Katsanis, N., Bostwick, B., Popp, B., Davis, E.E., Yang, Y, Stankiewicz, P., Khan, T.N., Szafranski, P., Slattery, L., Streff, H., Vetrini, F., Bernstein, J.A., Brown, C.W., Rosenfeld, J.A., Rednam, S., Scollon, S., Bergstrom, K.L., Parsons, D.W., Plon, S.E., Vieira, M.W., Quaio, C., Baratela, W.A.R., Guio, J.C.A., Armstrong, R., Mehta, S.G., Rump, P., Pfundt, R.P., Lewandowski, R., Fernandes, E.M., Shinde, D.N., Tang, S., Hoyer, J., Zweier, C., Reis, A., Bacino, C.A., Xiao, R., Breman, A.M., Smith, J.L., Katsanis, N., Bostwick, B., Popp, B., Davis, E.E., and Yang, Y

Abstract

Contains fulltext : 182555.pdf (publisher's version ) (Closed access), Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Published
2017

6. Reduced neurocognition in children who snore

Author

Kennedy, J.D., primary, Blunden, S., additional, Hirte, C., additional, Parsons, D.W., additional, Martin, A.J., additional, Crowe, E., additional, Williams, D., additional, Pamula, Y., additional, and Lushington, K., additional

Published
2004
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7. Efficacy of once‐daily tobramycin monotherapy for acute pulmonary exacerbations of cystic fibrosis: A preliminary study

Author

Master, Vahid, primary, Roberts, G.W., additional, Coulthard, K.P., additional, Baghurst, P.A., additional, Martin, A., additional, Roberts, M.E., additional, Onishko, C.R., additional, Martin, A.J., additional, Linke, R.J., additional, Holmes, M., additional, Jarvinen, A., additional, Kennedy, D., additional, Colebatch, K.A., additional, Hansman, D., additional, and Parsons, D.W., additional

Published
2001
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17. Airway gene therapy and cystic fibrosis.

Author

Parsons, D.W.

Subjects
*CYSTIC fibrosis, *GENE therapy, *PATHOGENIC microorganisms, *GENETIC transformation, *CLINICAL trials, *THERAPEUTICS
Abstract

Airway disease in cystic fibrosis (CF) is the major cause of death and is presently inadequately treatable, but genetic therapies offer the hope that such life-long disease will be curable, or at least satisfactorily treated. Normal pathogen defences that have evolved on airway surfaces also prevent the various gene vectors now available from producing effective gene transfer. Nevertheless, findings from basic research and human clinical trials are revealing how these barriers might be overcome or circumvented, with benefits to therapeutic efficacy and patient safety. Though progress is slower than expected or desired, the therapeutic rewards will be great when safe and effective gene therapy for CF airway disease becomes a clinical reality. [ABSTRACT FROM AUTHOR]

Published
2005
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18. Diagnosis of spinal muscular atrophy in an SMN non-deletion patient using a quantitative PCR screen and mutation analysis

Author

Parsons, D.W., McAndrew, P.E., Prior, T.W., Allinson, P.S., Jr, W.D. Parker, and Burghes, A.H.M.

Abstract

We report a child with clinical findings consistent with Werdnig-Hoffmann disease (spinal muscular atrophy type I) who was found not to have the homozygous absence of the survival motor neurone (SMNT) gene observed in ∼95% of spinal muscular atrophy patients. A quantitative PCR based dosage assay for SMNT copy number showed that this patient possessed a single copy of the SMNT gene. Heteroduplex and sequence analysis of the remaining copy of SMNT showed a 2 base pair deletion within exon 4 which produces a frameshift and premature termination of the deduced SMNT protein. This protocol of initial SMNT gene dosage analysis followed by mutation detection allows identification of SMA compound heterozygotes (patients lacking one copy of SMNT and having another mutation in their other copy), thereby increasing the sensitivity of SMA molecular diagnosis.

Published
1998

20. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

Author

Noreen Dhalla, Saianand Balu, Alexander Potapov, Yiling Lu, Antonio Iavarone, Roel G.W. Verhaak, Alessandro Perin, Bradley A. Murray, Lee Lichtenstein, Nils Gehlenborg, Zhenlin Ju, Simon G. Coetzee, Stephanie Weaver, Gaetano Finocchiaro, Susan M. Staugaitis, Scott Morris, Da Yang, Rosy Singh, Erik Zmuda, Wei Zhang, Aaron D. Black, Roger E. McLendon, J. Bradley Elder, J. Todd Auman, Arvind Rao, Harshad S. Mahadeshwar, Yunhu Wan, Liming Yang, Stacey Gabriel, Andreas Unterberg, Adam E. Flanders, Piotr A. Mieczkowski, Jianjiong Gao, Robert Penny, Andrew Wei Xu, Peter W. Laird, Gad Getz, Cynthia Taylor, Adrian Ally, Ilya Shmulevich, Tina Wong, Christopher M. McPherson, Heidi J. Sofia, Matthew G. Soloway, Jonna Grimsby, Caterina Giannini, Mark L. Cohen, Johanna Gardner, Semin Lee, Alan P. Hoyle, Jianhua Zhang, Thais S. Sabedot, Felicia Williams, Mia Grifford, Daniela Pretti da Cunha Tirapelli, David Van Den Berg, Margi Sheth, Ye Wu, Jenny Eschbacher, Marco A. Marra, Katherine A. Hoadley, Angeliki Pantazi, Chris Benz, Michael S. Noble, Christopher R. Pierson, Kristen M. Leraas, Roy Tarnuzzer, Suzanne Sifri, Huandong Sun, Greg Eley, Eyas M. Hattab, David I. Heiman, Rehan Akbani, Todd Pihl, Michael Parfenov, Erwin G. Van Meir, Jill S. Barnholtz-Sloan, Peggy Yena, Josh Stuart, Richard A. Moore, Toshinori Hinoue, Kelly Senecal, Andrew D. Cherniack, Donald W. Parsons, Rileen Sinha, Dennis T. Maglinte, Timothy A. Chan, Reanne Bowlby, Phuong L. Nguyen, Juok Cho, Andrew E. Sloan, Alexei Protopopov, Matthew Schniederjan, Yun Wang, Yuexin Liu, Rameen Beroukhim, Kristian Cibulskis, Ty Abel, Ronald E. Warnick, Sahil Seth, Richard A. Gibbs, Rebecca Duell, W. Kimryn Rathmell, Jay Bowen, Michael S. Lawrence, Darell D. Bigner, Mary McGraw, Wen-Bin Liu, Xiaojia Ren, Umadevi Veluvolu, Erin Curley, Lynda Chin, Andy Chu, Laila M. Poisson, Harindra Arachchi, Jean C. Zenklusen, Ardene Noss, Sue E. Bell, Karen Devine, Moiz S. Bootwalla, Rebecca Carlsen, David Mallery, Eric S. Lipp, Hailei Zhang, Bradley A. Ozenberger, Andrew J. Mungall, Amie Radenbaugh, Luciano Neder, Sol Katzman, Lisa Iype, Shaowu Meng, Wendi Barrett, S. Onur Sumer, Katie Dicostanzo, Mark Vitucci, Phillip H. Lai, Vsevolod Shurkhay, D. Neil Hayes, Jiabin Tang, Hui Shen, Christopher A. Bristow, Stefania Cuzzubbo, Quinn T. Ostrom, Yasin Senbabaoglu, Ruth Steele, Peter J. Park, Jacqueline E. Schein, Lior Pachter, Jia Liu, Payal Sipahimalani, Angela Hadjipanayis, Scott L. Carter, Donghui Tan, Travis I. Zack, Kristen Shimmel, Steven E. Schumacher, Leigh B. Thorne, Kenna R. Mills Shaw, Troy Shelton, Julien Baboud, Jianan Zhang, Olga Potapova, Stuart R. Jefferys, Andreas von Deimling, B. Arman Aksoy, Carrie Sougnez, Howard Colman, Tom Mikkelsen, Amanda Clarke, Houtan Noushmehr, Daniel Crain, Mark A. Jensen, D L Rotin, Stephen B. Baylin, Barry S. Taylor, Gordon Saksena, Benito Campos, Sudha Chudamani, Ouida Liu, Lisle E. Mose, Jonathan G. Seidman, Corbin D. Jones, Norman L. Lehman, Eric S. Lander, David Haussler, Franklin W. Huang, Nina Thiessen, Charles M. Perou, Gregory N. Fuller, Kosuke Yoshihara, C. Ryan Miller, Brenda Ayala, Dina Aziz, Sara Sadeghi, Cameron Brennan, Randy Mandt, Aditya Raghunathan, Jeffrey Roach, Robert A. Holt, Timothy J. Triche, Barbara Tabak, Kenneth Aldape, John N. Weinstein, Kevin Lau, Ady Kendler, Lee Cooper, Carlos Gilberto Carlotti, Siyuan Zheng, Isaac Joseph, Jason T. Huse, Steven J.M. Jones, Brady Bernard, Chip Stewart, Lixing Yang, Lisa Wise, A. Gordon Robertson, Ronglai Shen, Lisa Scarpace, Richard Kreisberg, Shiyun Ling, Michael Mayo, Jordonna Fulop, Cathy Brewer, Denise Brooks, Daniel E. Carlin, Nils Weinhold, Angela Tam, Beth Hermes, Kalle Leinonen, Giovanni Ciriello, Mahitha Vallurupalli, John A. Demchok, Bianca Pollo, Christel Herold-Mende, Rajan Jain, Liu Xi, Francesco DiMeco, Nilsa C. Ramirez, Tara M. Lichtenberg, Ashley Fehrenbach, Yingchun Liu, Miruna Balasundaram, Sofie R. Salama, Rivka R. Colen, Olena Morozova, Yussanne Ma, Zhining Wang, W. K. Alfred Yung, Scott R. VandenBerg, Esther Rheinbay, Junyuan Wu, Katayoon Kasaian, Tanja M. Davidsen, William A. Friedman, Kathy Smolenski, Yichao Sun, Anders Jacobsen, Chiara Calatozzolo, Matthew D. Wilkerson, Lucia Cuppini, Gordon B. Mills, Xingzhi Song, Joseph Paulauskis, Jaegil Kim, Pei Lin, Scott Frazer, William M. Lee, Evan O. Paull, Sheila A. Fisher, Carolyn M. Hutter, Janae V. Simons, Gene Barnett, Mara Rosenberg, Scot Waring, Timothy R. Fennell, Raju Kucherlapati, Christine Jungk, Martin L. Ferguson, Julie M. Gastier-Foster, Cathy Schilero, Yingli Wolinsky, Rohini Raman, Zack Sanborn, Ranabir Guin, Matthew Meyerson, Daniel J. Brat, Cheryl A. Palmer, Nikolaus Schultz, Erik P. Sulman, Eric Chuah, Mark E. Sherman, Theo A. Knijnenburg, Mitchel S. Berger, Lihua Zou, Hoon Kim, Daniel DiCara, Sam Ng, Joel S. Parker, Sheila Reynolds, Raffaele Nunziata, Daniel J. Weisenberger, Natalie Tasman, Chris Sander, Doug Voet, Yaron S.N. Butterfield, Brian P. O'Neill, Lori Boice, Brat D.J., Verhaak R.G.W., Aldape K.D., Yung W.K.A., Salama S.R., Cooper L.A.D., Rheinbay E., Miller C.R., Vitucci M., Morozova O., Robertson A.G., Noushmehr H., Laird P.W., Cherniack A.D., Akbani R., Huse J.T., Ciriello G., Poisson L.M., Barnholtz-Sloan J.S., Berger M.S., Brennan C., Colen R.R., Colman H., Flanders A.E., Giannini C., Grifford M., Iavarone A., Jain R., Joseph I., Kim J., Kasaian K., Mikkelsen T., Murray B.A., O'Neill B.P., Pachter L., Parsons D.W., Sougnez C., Sulman E.P., Vandenberg S.R., Van Meir E.G., Von Deimling A., Zhang H., Crain D., Lau K., Mallery D., Morris S., Paulauskis J., Penny R., Shelton T., Sherman M., Yena P., Black A., Bowen J., Dicostanzo K., Gastier-Foster J., Leraas K.M., Lichtenberg T.M., Pierson C.R., Ramirez N.C., Taylor C., Weaver S., Wise L., Zmuda E., Davidsen T., Demchok J.A., Eley G., Ferguson M.L., Hutter C.M., Shaw K.R.M., Ozenberger B.A., Sheth M., Sofia H.J., Tarnuzzer R., Wang Z., Yang L., Zenklusen J.C., Ayala B., Baboud J., Chudamani S., Jensen M.A., Liu J., Pihl T., Raman R., Wan Y., Wu Y., Ally A., Auman J.T., Balasundaram M., Balu S., Baylin S.B., Beroukhim R., Bootwalla M.S., Bowlby R., Bristow C.A., Brooks D., Butterfield Y., Carlsen R., Carter S., Chin L., Chu A., Chuah E., Cibulskis K., Clarke A., Coetzee S.G., Dhalla N., Fennell T., Fisher S., Gabriel S., Getz G., Gibbs R., Guin R., Hadjipanayis A., Hayes D.N., Hinoue T., Hoadley K., Holt R.A., Hoyle A.P., Jefferys S.R., Jones S., Jones C.D., Kucherlapati R., Lai P.H., Lander E., Lee S., Lichtenstein L., Ma Y., Maglinte D.T., Mahadeshwar H.S., Marra M.A., Mayo M., Meng S., Meyerson M.L., Mieczkowski P.A., Moore R.A., Mose L.E., Mungall A.J., Pantazi A., Parfenov M., Park P.J., Parker J.S., Perou C.M., Protopopov A., Ren X., Roach J., Sabedot T.S., Schein J., Schumacher S.E., Seidman J.G., Seth S., Shen H., Simons J.V., Sipahimalani P., Soloway M.G., Song X., Sun H., Tabak B., Tam A., Tan D., Tang J., Thiessen N., Triche T., Van Den Berg D.J., Veluvolu U., Waring S., Weisenberger D.J., Wilkerson M.D., Wong T., Wu J., Xi L., Xu A.W., Zack T.I., Zhang J., Aksoy B.A., Arachchi H., Benz C., Bernard B., Carlin D., Cho J., DiCara D., Frazer S., Fuller G.N., Gao J., Gehlenborg N., Haussler D., Heiman D.I., Iype L., Jacobsen A., Ju Z., Katzman S., Kim H., Knijnenburg T., Kreisberg R.B., Lawrence M.S., Lee W., Leinonen K., Lin P., Ling S., Liu W., Liu Y., Lu Y., Mills G., Ng S., Noble M.S., Paull E., Rao A., Reynolds S., Saksena G., Sanborn Z., Sander C., Schultz N., Senbabaoglu Y., Shen R., Shmulevich I., Sinha R., Stuart J., Sumer S.O., Sun Y., Tasman N., Taylor B.S., Voet D., Weinhold N., Weinstein J.N., Yang D., Yoshihara K., Zheng S., Zhang W., Zou L., Abel T., Sadeghi S., Cohen M.L., Eschbacher J., Hattab E.M., Raghunathan A., Schniederjan M.J., Aziz D., Barnett G., Barrett W., Bigner D.D., Boice L., Brewer C., Calatozzolo C., Campos B., Carlotti C.G., Chan T.A., Cuppini L., Curley E., Cuzzubbo S., Devine K., DiMeco F., Duell R., Elder J.B., Fehrenbach A., Finocchiaro G., Friedman W., Fulop J., Gardner J., Hermes B., Herold-Mende C., Jungk C., Kendler A., Lehman N.L., Lipp E., Liu O., Mandt R., McGraw M., Mclendon R., McPherson C., Neder L., Nguyen P., Noss A., Nunziata R., Ostrom Q.T., Palmer C., Perin A., Pollo B., Potapov A., Potapova O., Rathmell W.K., Rotin D., Scarpace L., Schilero C., Senecal K., Shimmel K., Shurkhay V., Sifri S., Singh R., Sloan A.E., Smolenski K., Staugaitis S.M., Steele R., Thorne L., Tirapelli D.P.C., Unterberg A., Vallurupalli M., Wang Y., Warnick R., Williams F., Wolinsky Y., Bell S., Rosenberg M., Stewart C., Huang F., Grimsby J.L., and Radenbaugh A.J.

Subjects
Adult, Male, Pathology, medicine.medical_specialty, IDH1, Adolescent, Kaplan-Meier Estimate, 1p/19q Codeletion, Biology, Article, Glioma, Molecular genetics, Grade II Glioma, medicine, Cluster Analysis, Humans, neoplasms, Exome, ATRX, Proportional Hazards Models, Aged, Cluster Analysi, DNA, Neoplasm, Sequence Analysis, DNA, General Medicine, Middle Aged, Genes, p53, medicine.disease, Chromosomes, Human, Pair 1, Mutation, Proportional Hazards Model, Cancer research, GLIOMA, Female, Oligodendroglioma, Neoplasm Grading, Glioblastoma, Chromosomes, Human, Pair 19, Human, Signal Transduction
Abstract

BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.)

Published
2015
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