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11 results on '"Jabado N."'

1. A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method

Author

Walker, D. A., Liu, J., Kieran, M., Jabado, N., Picton, S., Packer, R., Rose, C. S. t., Van Meeteren, A. S., Carvalho, A., Van Damme, A., Depreitere, B., Gustavsson, B., Due Tonnessen, B. J., Bertozzi Salamon, A. I., Brentrup, A., Raybaud, C., Jones, C., Dufour, C., Dorfer, C., Sainte Rose, C., Malluci, C., Hargrave, D., Walker, D., Van Vuurden, D., De Carli, E., Bouffet, E., Van Calenbergh, F., Frappaz, D., Frassanito, P., Goodrich, J., Baechli, H., Grill, J., Ternier, J., Cappelen, J., Caird, J., Pereira, J., Riffaud, L., Baroncini, M., Walker, M., Ozek, M., Nysom, K., Varlet, P., Goodden, J., Bertolini, P., Perilongo, Giorgio, Mercier, P., Grundy, R., Kortmann, R. D., Pfister, S., Constantini, S., Sgouros, S., Holm, S., Czech, T., Merchant, T., Stokland, T., Ridola, V., and Vandertop, P.

Subjects
Cancer Research, medicine.medical_specialty, Consensus, medicine.medical_treatment, Neurosurgery, Glioma, Biopsy, medicine, Brain Stem Neoplasms, Humans, Neurofibromatosis, Child, medicine.diagnostic_test, business.industry, General surgery, Astrocytoma, medicine.disease, Surgery, Radiation therapy, Clinical trial, Oncology, Practice Guidelines as Topic, Basic and Translational Investigations, Neurology (clinical), Neoplasm Grading, business, Risk assessment
Abstract

Astrocytic tumors account for 42% of childhood brain tumors, arising in all anatomical regions and associated with neurofibromatosis type 1 (NF1) in 15%. Anatomical site determines the degree and risk of resectability; the more complete resection, the better the survival rates. New biological markers and modern radiotherapy techniques are altering the risk assessments of clinical decisions for tumor resection and biopsy. The increasingly distinct pediatric neuro-oncology multidisciplinary team (PNMDT) is developing a distinct evidence base. A multidisciplinary consensus conference on pediatric neurosurgery was held in February 2011, where 92 invited participants reviewed evidence for clinical management of hypothalamic chiasmatic glioma (HCLGG), diffuse intrinsic pontine glioma (DIPG), and high-grade glioma (HGG). Twenty-seven statements were drafted and subjected to online Delphi consensus voting by participants, seeking >70% agreement from >60% of respondents; where

Published
2013
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2. Sam68 association with p120GAP in CD4+ T cells is dependent on CD4 molecule expression

Author

Jabado, N., Sebastien Jauliac, Pallier, A., Bernard, F., Fischer, A., Hivroz, C., Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Jauliac, Sebastien, and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
CD4-Positive T-Lymphocytes, MESH: GTP Phosphohydrolases, Immunology, MESH: Antigens, CD4, MESH : Phospholipas, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: GTPase-Activating Proteins, Lymphocyte Activation, Lymphoma, T-Cell, MESH : Lymphoma, T-Cell, GTP Phosphohydrolases, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH : Cells, Cultured, Tumor Cells, Cultured, Immunology and Allergy, Humans, Phosphorylation, MESH : Phospholipase C, MESH: Lymphocyte Activation, MESH : Lymphocyte Activation, Cells, Cultured, Adaptor Proteins, Signal Transducing, MESH : Isoenzymes, MESH: Lymphocyte Specific Protein Tyrosine Kinase p56(lck), MESH: Humans, Phospholipase C gamma, MESH : Humans, GTPase-Activating Proteins, MESH: Phospholipas, MESH : GTPase-Activating Proteins, MESH: CD4-Positive T-Lymphocytes, Proteins, RNA-Binding Proteins, DNA-Binding Proteins, Isoenzymes, MESH : Lymphocyte Specific Protein Tyrosine Kinase p56(lck), src-Family Kinases, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), ras GTPase-Activating Proteins, MESH : CD4-Positive T-Lymphocytes, Type C Phospholipases, CD4 Antigens, MESH: Phospholipase C, MESH: Isoenzymes, ras Proteins, MESH : Antigens, CD4, MESH: Lymphoma, T-Cell, MESH : GTP Phosphohydrolases, MESH: Cells, Cultured
Abstract

p120 GTPase-activating protein (p120GAP) is a major negative regulator of p21ras activity in several cell types including T cells. Catalytic activity of this enzyme is regulated in part by its interaction with several associated tyrosine-phosphorylated proteins. Sam68 was initially described as associated with p120GAP. It has been further established that Sam68 is a substrate of src kinases in mitosis and that it is not associated with p120GAP in transformed fibroblasts. We describe herein that Sam68 associates with p120GAP and PLCγ1 in human mature T cells and in a T cell line expressing the CD4 molecule HUT78 CD4+. This association is present in nonactivated cells and increases after anti-CD3 activation. It is dependent on CD4 expression and, in part, on the association of CD4 with p56lck, as shown by the strongly decreased association of Sam68 with p120GAP in the CD4− mutants, HUT78 CD4−, and by the reduced association of Sam68 with both p120GAP and p56lck in the HUT78 T cell line expressing a CD4 mutant unable to interact with p56lck, HUT78 C420/22. We propose that recruitment of Sam68, via CD4/p56lck, to the inner face of the plasma membrane may permit, via its docking properties, the correct association of key signaling molecules including PLCγ1 and p120GAP. This formation of transduction modules will enable the activation of different signaling cascades including the p21ras pathway and an array of downstream events, ultimately leading to T cell activation.

Published
1998

3. Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors

Author

Jabado N, Er, Graeff-Meeder, Marina Cavazzana, Haddad E, Le Deist F, Benkerrou M, Dufourcq R, Caillat S, Blanche S, and Fischer A

Subjects
Adult, Male, Adolescent, Histiocytosis, Non-Langerhans-Cell, Chimera, Histocompatibility Testing, Immunology, Cell Biology, Hematology, Middle Aged, Biochemistry, surgical procedures, operative, Treatment Outcome, Child, Preschool, Humans, Female, Child, Bone Marrow Transplantation
Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

Published
1998

4. CD4 ligands inhibit the formation of multifunctional transduction complexes involved in T cell activation

Author

Jabado N, Pallier A, Le Deist F, Bernard F, Fischer A, and Claire Hivroz

Subjects
T-Lymphocytes, Immunology, HIV Envelope Protein gp120, Protein Serine-Threonine Kinases, Ligands, Lymphocyte Activation, HIV Envelope Protein gp160, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins, Immunology and Allergy, Humans, Phosphorylation, Mitogen-Activated Protein Kinase 1, Phospholipase C gamma, GTPase-Activating Proteins, Antibodies, Monoclonal, Proteins, Isoenzymes, Proto-Oncogene Proteins c-raf, ras GTPase-Activating Proteins, Type C Phospholipases, CD4 Antigens, Calcium-Calmodulin-Dependent Protein Kinases, Calcium, Protein Binding, Signal Transduction
Abstract

Ligands binding to the CD4 molecule can inhibit TCR-mediated T cell activation. We have previously reported that transcription factors regulating the expression of the IL-2 gene, NF-AT, NF-kappaB, and AP-1, are targets of this inhibitory effect in an in vitro model using peripheral human CD4+ T cells activated by a CD3 mAb. Two T cell activation pathways involved in the regulation of these transcription factors, calcium flux and the p21ras pathway, were investigated as potential targets. Binding of HIV envelope glycoprotein gp160/gp120 or a CD4 mAb to the CD4+ T cells, prior to TCR/CD3 activation, inhibited the intracellular calcium elevation. This event strongly suggested an inhibition of PLCgamma1 activity. Tyrosine phosphorylation of PLCgamma1, induced by CD3 activation, was not affected, but its association with tyrosine-phosphorylated proteins, including a 62-kDa protein, was disrupted. This PLCgamma1-associated p62 was found to be immunoreactive to p62-Sam68 Abs. The activation-induced phosphorylation of two p21ras effectors, Raf-1 and Erk2, was inhibited by the CD4 ligands, indirectly pointing to inhibition of the p21ras activation pathway. In addition, we demonstrate that TCR activation of normal CD4+ T cells induced the formation of p120GAP and PLCgamma1-containing complexes. These complexes also contain other unidentified proteins. CD4 ligand binding induced a defective formation of these transduction complexes. This may result in inefficient signaling, partially accounting for the inhibitory effects of the CD4 ligands on both p21ras and calcium-activation pathways.

Published
1997

5. Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak-Higashi syndrome

Author

Stephanie DOGNIAUX, Barrat F, Pastural E, Le Deist F, Goyo-Rivas J, Jabado N, Benkerrou M, Seger R, Vilmer E, Beullier G, Schwarz K, Fischer A, and de Saint Basile G

Subjects
Adult, Male, Terminator Regions, Genetic, Epstein-Barr Virus Infections, Adolescent, Reverse Transcriptase Polymerase Chain Reaction, Vesicular Transport Proteins, Infant, Proteins, Lymphoproliferative Disorders, Child, Preschool, Humans, Female, RNA, Messenger, Chediak-Higashi Syndrome, Child, Codon, Lysosomes, Sequence Deletion
Abstract

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder in which an immune deficiency occurs in association with pigmentation abnormalities. Most patients who do not undergo bone marrow transplantation die of a lymphoproliferative syndrome, though some patients with CHS have a relatively milder clinical course of the disease. The large size of the LYST gene, defective in CHS, has made it difficult to screen for mutations in a large number of patients. Only 8 mutations have been identified so far, and all lead to a truncated LYST protein. We conducted protein truncation tests on this gene in 8 patients with CHS. Different LYST mutations were identified in all subjects through this approach, strengthening the observation of a high frequency of truncated LYST proteins as the genetic cause of CHS.

9. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Author

Anne Jouvet, Ana Gutiérrez-Fernández, Namal Abeysundara, Olivier Ayrault, Vijay Ramaswamy, Charles G. Eberhart, Jennifer A. Chan, Johan M. Kros, Xiaochong Wu, Sachin Kumar, Seung-Ki Kim, Maria C. Vladoiu, Noriyuki Kijima, Xose S. Puente, Ian F. Pollack, Robert J. Wechsler-Reya, Boleslaw Lach, Almos Klekner, Ander Diaz-Navarro, Claudia C. Faria, Lincoln Stein, Nicole Gauer, Enrique López-Aguilar, Nada Jabado, Amulya A. Nageswara Rao, Livia Garzia, David Malkin, Stefan M. Pfister, Jiannis Ragoussis, Maura Massimino, James M. Olson, Caterina Giannini, Hamza Farooq, Pim J. French, Florence M.G. Cavalli, Anna Goldenberg, John A. Calarco, Joshua B. Rubin, Maria Luisa Garrè, Betty Luu, László Bognár, Weifan Dong, Shimin Shuai, Antoine Forget, Jun Wang, Ichiyo Shibahara, Pasqualino De Antonellis, William A. Weiss, Marco A. Marra, Lola B. Chambless, Patryk Skowron, Wiesława Grajkowska, Jiao Zhang, Ali Momin, Erwin G. Van Meir, Michelle Fèvre-Montange, Rajeev Vibhakar, Ho Keung Ng, David Przelicki, Hiromichi Suzuki, Kyle Juraschka, Craig Daniels, A. Sorana Morrissy, Toshihiro Kumabe, Xi Huang, Wai Sang Poon, Swneke D. Bailey, Michael D. Taylor, Pathology, Neurology, Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France. 4Université Paris Sud, Université Paris- Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France., Institut Curie [Paris], Suzuki H., Kumar S.A., Shuai S., Diaz-Navarro A., Gutierrez-Fernandez A., De Antonellis P., Cavalli F.M.G., Juraschka K., Farooq H., Shibahara I., Vladoiu M.C., Zhang J., Abeysundara N., Przelicki D., Skowron P., Gauer N., Luu B., Daniels C., Wu X., Forget A., Momin A., Wang J., Dong W., Kim S.-K., Grajkowska W.A., Jouvet A., Fevre-Montange M., Garre M.L., Nageswara Rao A.A., Giannini C., Kros J.M., French P.J., Jabado N., Ng H.-K., Poon W.S., Eberhart C.G., Pollack I.F., Olson J.M., Weiss W.A., Kumabe T., Lopez-Aguilar E., Lach B., Massimino M., Van Meir E.G., Rubin J.B., Vibhakar R., Chambless L.B., Kijima N., Klekner A., Bognar L., Chan J.A., Faria C.C., Ragoussis J., Pfister S.M., Goldenberg A., Wechsler-Reya R.J., Bailey S.D., Garzia L., Morrissy A.S., Marra M.A., Huang X., Malkin D., Ayrault O., Ramaswamy V., Puente X.S., Calarco J.A., Stein L., Taylor M.D., Repositório da Universidade de Lisboa, Suzuki, H., Kumar, S. A., Shuai, S., Diaz-Navarro, A., Gutierrez-Fernandez, A., De Antonellis, P., Cavalli, F. M. G., Juraschka, K., Farooq, H., Shibahara, I., Vladoiu, M. C., Zhang, J., Abeysundara, N., Przelicki, D., Skowron, P., Gauer, N., Luu, B., Daniels, C., Wu, X., Forget, A., Momin, A., Wang, J., Dong, W., Kim, S. -K., Grajkowska, W. A., Jouvet, A., Fevre-Montange, M., Garre, M. L., Nageswara Rao, A. A., Giannini, C., Kros, J. M., French, P. J., Jabado, N., Ng, H. -K., Poon, W. S., Eberhart, C. G., Pollack, I. F., Olson, J. M., Weiss, W. A., Kumabe, T., Lopez-Aguilar, E., Lach, B., Massimino, M., Van Meir, E. G., Rubin, J. B., Vibhakar, R., Chambless, L. B., Kijima, N., Klekner, A., Bognar, L., Chan, J. A., Faria, C. C., Ragoussis, J., Pfister, S. M., Goldenberg, A., Wechsler-Reya, R. J., Bailey, S. D., Garzia, L., Morrissy, A. S., Marra, M. A., Huang, X., Malkin, D., Ayrault, O., Ramaswamy, V., Puente, X. S., Calarco, J. A., Stein, L., Taylor, M. D., and Olivier, AYRAULT

Subjects
0301 basic medicine, Adult, Adolescent, RNA Splicing, [SDV]Life Sciences [q-bio], Biology, Article, 03 medical and health sciences, 0302 clinical medicine, GLI2, RNA, Small Nuclear, medicine, Humans, G%29+of+U1+spliceosomal+small+nuclear+RNAs+%28snRNAs%29%22">subgroups of medulloblastoma, recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs), Hedgehog Proteins, Sonic hedgehog, Cerebellar Neoplasms, Gene, ComputingMilieux_MISCELLANEOUS, Medulloblastoma, Multidisciplinary, Cerebellar Neoplasm, Alternative splicing, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Alternative Splicing, 030104 developmental biology, PTCH1, RNA Splice Site, 030220 oncology & carcinogenesis, RNA splicing, Mutation, Cancer research, biology.protein, RNA Splice Sites, Hedgehog Protein, Small nuclear RNA, Human
Abstract

© The Author(s), under exclusive licence to Springer Nature Limited 2019, In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only

Published
2019

10. Intertumoral Heterogeneity within Medulloblastoma Subgroups

Author

Luca Massimi, Caterina Giannini, Betty Luu, Cynthia Hawkins, Byung Kyu Cho, James T. Rutka, G. Yancey Gillespie, Timothy E. Van Meter, Almos Klekner, Young Shin Ra, Carolina Nor, Anna Goldenberg, Rajeev Vibhakar, Hideo Nakamura, Gaetano Finocchiaro, Massimo Zollo, John Peacock, Marta Perek-Polnik, Keren Isaev, Alvaro Lassaletta, Amulya A. Nageswara Rao, Florence M.G. Cavalli, Maura Massimino, Livia Garzia, Jüri Reimand, Charles G. Eberhart, Maryam Fouladi, Enrique López-Aguilar, Annie Huang, Cécile Faure-Conter, Gary D. Bader, Jaume Mora, Ho Keung Ng, James M. Olson, Jennifer A. Chan, Erwin G. Van Meir, Daniela Pretti da Cunha Tirapelli, Hamza Farooq, Fernando Chico Ponce de León, Linda M. Liau, Kay Ka Wai Li, Shenandoah Robinson, Anne Jouvet, Tomoko Shofuda, José Pimentel, Reid C. Thompson, Yuan Yao Thompson, Ian F. Pollack, Nada Jabado, Boleslaw Lach, Pim J. French, Joshua B. Rubin, Eric Bouffet, Alexandre Vasiljevic, Ali G. Saad, Michael K. Cooper, Satoru Osuka, Peter B. Dirks, Jaroslav Sterba, Johan M. Kros, Claudia C. Faria, Kyu-Chang Wang, Seung-Ki Kim, Shin Jung, Craig Daniels, A. Sorana Morrissy, Ladislav Rampášek, Andrew R. Hallahan, Sarah Leary, Wiesława Grajkowska, Uri Tabori, Marc Remke, Samer K. Elbabaa, Michael D. Taylor, Andrew S. Moore, Toshihiro Kumabe, Mario Perezpeña-Diazconti, Vijay Ramaswamy, Ronald L. Hamilton, Claudia M. Kuzan-Fischer, Marie Lise C. van Veelen, Helen Wheeler, Michal Zapotocky, Ji Yeoun Lee, David Shih, Jeffrey R. Leonard, Karel Zitterbart, Carlos Gilberto Carlotti, Steffen Albrecht, Jonathon Torchia, Peter Hauser, Ute Bartels, William A. Weiss, Sameer Agnihotri, Lola B. Chambless, Neurosurgery, Pathology, Neurology, Cavalli, Fmg, Remke, M, Rampasek, L, Peacock, J, Shih, Djh, Luu, B, Garzia, L, Torchia, J, Nor, C, Morrissy, A, Agnihotri, S, Thompson, Yy, Kuzan-Fischer, Cm, Farooq, H, Isaev, K, Daniels, C, Cho, Bk, Kim, Sk, Wang, Kc, Lee, Jy, Grajkowska, Wa, Perek-Polnik, M, Vasiljevic, A, Faure-Conter, C, Jouvet, A, Giannini, C, Nageswara Rao, Aa, Li, Kkw, Ng, Hk, Eberhart, Cg, Pollack, If, Hamilton, Rl, Gillespie, Gy, Olson, Jm, Leary, S, Weiss, Wa, Lach, B, Chambless, Lb, Thompson, Rc, Cooper, Mk, Vibhakar, R, Hauser, P, van Veelen, Mc, Kros, Jm, French, Pj, Ra, Y, Kumabe, T, López-Aguilar, E, Zitterbart, K, Sterba, J, Finocchiaro, G, Massimino, M, Van Meir, Eg, Osuka, S, Shofuda, T, Klekner, A, Zollo, M, Leonard, Jr, Rubin, Jb, Jabado, N, Albrecht, S, Mora, J, Van Meter, Te, Jung, S, Moore, A, Hallahan, Ar, Chan, Ja, Tirapelli, Dpc, Carlotti, Cg, Fouladi, M, Pimentel, J, Faria, Cc, Saad, Ag, Massimi, L, Liau, Lm, Wheeler, H, Nakamura, H, Elbabaa, Sk, Perezpeña-Diazconti, M, Chico Ponce de León, F, Robinson, S, Zapotocky, M, Lassaletta, A, Huang, Weiping, Hawkins, Ce, Tabori, U, Bouffet, E, Bartels, U, Dirks, Pb, Rutka, Jt, Bader, Gd, Reimand, J, Goldenberg, A, Ramaswamy, V, Taylor, Md, Cavalli F.M.G., Remke M., Rampasek L., Peacock J., Shih D.J.H., Luu B., Garzia L., Torchia J., Nor C., Morrissy A.S., Agnihotri S., Thompson Y.Y., Kuzan-Fischer C.M., Farooq H., Isaev K., Daniels C., Cho B.-K., Kim S.-K., Wang K.-C., Lee J.Y., Grajkowska W.A., Perek-Polnik M., Vasiljevic A., Faure-Conter C., Jouvet A., Giannini C., Nageswara Rao A.A., Li K.K.W., Ng H.-K., Eberhart C.G., Pollack I.F., Hamilton R.L., Gillespie G.Y., Olson J.M., Leary S., Weiss W.A., Lach B., Chambless L.B., Thompson R.C., Cooper M.K., Vibhakar R., Hauser P., van Veelen M.-L.C., Kros J.M., French P.J., Ra Y.S., Kumabe T., Lopez-Aguilar E., Zitterbart K., Sterba J., Finocchiaro G., Massimino M., Van Meir E.G., Osuka S., Shofuda T., Klekner A., Zollo M., Leonard J.R., Rubin J.B., Jabado N., Albrecht S., Mora J., Van Meter T.E., Jung S., Moore A.S., Hallahan A.R., Chan J.A., Tirapelli D.P.C., Carlotti C.G., Fouladi M., Pimentel J., Faria C.C., Saad A.G., Massimi L., Liau L.M., Wheeler H., Nakamura H., Elbabaa S.K., Perezpena-Diazconti M., Chico Ponce de Leon F., Robinson S., Zapotocky M., Lassaletta A., Huang A., Hawkins C.E., Tabori U., Bouffet E., Bartels U., Dirks P.B., Rutka J.T., Bader G.D., Reimand J., Goldenberg A., Ramaswamy V., and Taylor M.D.

Subjects
0301 basic medicine, Cancer Research, medulloblastoma, CURRENT CONSENSUS, copy number, Bioinformatics, subgroups, Cohort Studies, Individual data, Cluster Analysis, R PACKAGE, Precision Medicine, GENECHIP DATA, Sonic hedgehog, ADULT MEDULLOBLASTOMA, DNA Copy Number Variation, Cancer, Pediatric, Genomics, methylation, CANCER, 3. Good health, Oncology, DNA methylation, Human, Pediatric Research Initiative, DNA Copy Number Variations, Pediatric Cancer, Oncology and Carcinogenesis, Computational biology, Biology, Article, CLASSIFICATION, Homogeneous clusters, 03 medical and health sciences, Rare Diseases, Genetics, medicine, Humans, Oncology & Carcinogenesis, Cerebellar Neoplasms, RECURRENCE, neoplasms, Medulloblastoma, Cluster Analysi, gene expression, MUTATIONS, subgroup, Gene Expression Profiling, Human Genome, Neurosciences, integrative clustering, DNA Methylation, medicine.disease, Precision medicine, MEDULOBLASTOMA, Brain Disorders, nervous system diseases, Brain Cancer, Gene expression profiling, stomatognathic diseases, 030104 developmental biology, Genomic, biology.protein, MOLECULAR SUBGROUPS, GENOMIC DATA, Cohort Studie
Abstract

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Published
2017

11. Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Author

Didier Frappaz, Shiyang Wang, Matija Snuderl, Catriona Ling, Rahul Krishnatry, Romain Perbet, Elizabeth Finch, David Sumerauer, Alexandre Vasiljevic, Nataliya Zhukova, Annie Huang, A. T. Chan, Matthew Mistry, Zhi Feng Shi, Cecile Faure Conter, Adam Fleming, Jean Mulcahy-Levy, Nicholas K. Foreman, Matthias A. Karajannis, Ibrahim Qaddoumi, Vijay Ramaswamy, Amulya A. Nageswara Rao, Julie H. Harreld, Anne Sophie Carret, Roger J. Packer, Samantha Mascelli, Cheng-Ying Ho, Theodore Nicolaides, Eric Bouffet, Shayna Zelcer, David W. Ellison, Mark W. Kieran, Keith L. Ligon, Sarah Leary, Ute Bartels, Tara McKeown, Sabine Mueller, Maria Luisa Garrè, Scott Ryall, Bev Wilson, Peter B. Dirks, Michael D. Taylor, Peter Hauser, James T. Rutka, Lenka Krskova, Michal Zapotocky, Courtney A. Crane, Ho Keung Ng, Ofelia Cruz, Carmen de Torres, Ying Mao, Uri Tabori, Alvaro Lassaletta, Marion Honnorat, Anthony Arnoldo, Paolo Nozza, David D. Eisenstat, Valerie Larouche, Alessandro Raso, Shiyi Chen, Nada Jabado, Karen Silva, Ruth G. Tatevossian, Cynthia Hawkins, Ana Guerreiro Stucklin, Jim Loukides, Caterina Giannini, James Dalton, Lassaletta A., Zapotocky M., Mistry M., Ramaswamy V., Honnorat M., Krishnatry R., Stucklin A.G., Zhukova N., Arnoldo A., Ryall S., Ling C., McKeown T., Loukides J., Cruz O., De Torres C., Ho C.-Y., Packer R.J., Tatevossian R., Qaddoumi I., Harreld J.H., Dalton J.D., Mulcahy-Levy J., Foreman N., Karajannis M.A., Wang S., Snuderl M., Rao A.N., Giannini C., Kieran M., Ligon K.L., Garre M.L., Nozza P., Mascelli S., Raso A., Mueller S., Nicolaides T., Silva K., Perbet R., Vasiljevic A., Conter C.F., Frappaz D., Leary S., Crane C., Chan A., Ng H.-K., Shi Z.-F., Mao Y., Finch E., Eisenstat D., Wilson B., Carret A.S., Hauser P., Sumerauer D., Krskova L., Larouche V., Fleming A., Zelcer S., Jabado N., Rutka J.T., Dirks P., Taylor M.D., Chen S., Bartels U., Huang A., Ellison D.W., Bouffet E., Hawkins C., and Tabori U.

Subjects
Oncology, Male, Cancer Research, Pathology, medicine.medical_treatment, Pediatrics, Cohort Studies, 0302 clinical medicine, CDKN2A, Brain Stem Neoplasms, Child, Brain Neoplasms, Glioma, Prognosis, 030220 oncology & carcinogenesis, Child, Preschool, Cohort, Female, Human, Cohort study, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Adolescent, Prognosi, Brain Neoplasm, 03 medical and health sciences, Internal medicine, Original Reports, medicine, Adjuvant therapy, Humans, Diencephalon, Preschool, neoplasms, Brain Stem Neoplasm, Chemotherapy, business.industry, Infant, medicine.disease, digestive system diseases, BRAF V600E, Mutation, Cohort Studie, Neoplasm Grading, business, human activities, 030217 neurology & neurosurgery, Progressive disease
Abstract

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Published
2017

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