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1. The genomic landscape of dysembryoplastic neuroepithelial tumours and a comprehensive analysis of recurrent cases

Author

Pagès, Mélanie, Debily, Marie-Anne, Fina, Frédéric, Jones, David, Saffroy, Raphael, Castel, David, Blauwblomme, Thomas, Métais, Alice, Bourgeois, Marie, Lechapt-Zalcman, Emmanuèle, Tauziède-Espariat, Arnault, Andreiuolo, Felipe, Chrétien, Fabrice, Grill, Jacques, Boddaert, Nathalie, Figarella‑branger, Dominique, Beroukhim, Rameen, Varlet, Pascale, Debily, Marie‐anne, Institut de neurophysiopathologie (INP), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Histology, MESH: Humans, Brain Neoplasms, MESH: Genomics, [SDV]Life Sciences [q-bio], MESH: Retrospective Studies, [SDV.CAN]Life Sciences [q-bio]/Cancer, Genomics, Glioma, paediatric low-grade gliomas, Neoplasms, Neuroepithelial, Pathology and Forensic Medicine, MESH: Neoplasms, Neuroepithelial, MESH: Glioma, FGFR1, Neurology, molecular pathology, Physiology (medical), MESH: Brain Neoplasms, DNA methylation profiling, glioneuronal tumours, Humans, Neurology (clinical), dysembryoplastic neuroepithelial tumours, Retrospective Studies
Abstract

Dysembryoplastic neuroepithelial tumour (DNT) is a glioneuronal tumour that is challenging to diagnose, with a wide spectrum of histological features. Three histopathological patterns have been described: specific DNTs (both the simple form and the complex form) comprising the specific glioneuronal element, and also the non-specific/diffuse form which lacks it, and has unclear phenotype-genotype correlations with numerous differential diagnoses.We used targeted methods (immunohistochemistry, fluorescence in situ hybridisation and targeted sequencing) and large-scale genomic methodologies including DNA methylation profiling to perform an integrative analysis to better characterise a large retrospective cohort of 82 DNTs, enriched for tumours that showed progression on imaging.We confirmed that specific DNTs are characterised by a single driver event with a high frequency of FGFR1 variants. However, a subset of DNA methylation-confirmed DNTs harbour alternative genomic alterations to FGFR1 duplication/mutation. We also demonstrated that a subset of DNTs sharing the same FGFR1 alterations can show in situ progression. In contrast to the specific forms, "non-specific/diffuse DNTs" corresponded to a heterogeneous molecular group encompassing diverse, newly-described, molecularly distinct entities.Specific DNT is a homogeneous group of tumours sharing characteristics of paediatric low-grade gliomas: a quiet genome with a recurrent genomic alteration in the RAS-MAPK signalling pathway, a distinct DNA methylation profile and a good prognosis but showing progression in some cases. The "non-specific/diffuse DNTs" subgroup encompasses various recently described histomolecular entities, such as PLNTY and diffuse astrocytoma, MYB or MYBL1 altered.

Published
2022

2. Additional file 1 of Posterior fossa ependymoma H3 K27-mutant: an integrated radiological and histomolecular tumor analysis

Author

Mariet, Cassandra, Castel, David, Grill, Jacques, Saffroy, Raphaël, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Llamas-Guttierrez, Francisco, Chappé, Céline, Puget, Stéphanie, Hasty, Lauren, Chrétien, Fabrice, Métais, Alice, Varlet, Pascale, and Tauziède-Espariat, Arnault

Abstract

Additional file 1: Figure 1. Copy number profiles of cases of the cohort.

Published
2022
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3. Additional file 2 of Posterior fossa ependymoma H3 K27-mutant: an integrated radiological and histomolecular tumor analysis

Author

Mariet, Cassandra, Castel, David, Grill, Jacques, Saffroy, Raphaël, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Llamas-Guttierrez, Francisco, Chappé, Céline, Puget, Stéphanie, Hasty, Lauren, Chrétien, Fabrice, Métais, Alice, Varlet, Pascale, and Tauziède-Espariat, Arnault

Abstract

Additional file 2: Table 1. Summary of clinicopathological features of the H3K27M-mutant diffuse midline gliomas with ependymal tumor patients of the current study.

Published
2022
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4. Additional file 1 of A novel LARGE1-AFF2 fusion expanding the molecular alterations associated with the methylation class of neuroepithelial tumors with PATZ1 fusions

Author

Tauzi��de-Espariat, Arnault, Chotard, Guillaume, le Loarer, Fran��ois, Baud, Jessica, Azmani, Rihab, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Icher-de-Bouyn, C��line, Gimbert, Edouard, Hasty, Lauren, M��tais, Alice, Chr��tien, Fabrice, and Varlet, Pascale

Abstract

Additional file 1. Table S1. Summary of clinical, histopathological and molecular data of CNS PATZ1-fused tumors reported in the literature

Published
2022
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5. A novel LARGE1-AFF2 fusion expanding the molecular alterations associated with the methylation class of neuroepithelial tumors with PATZ1 fusions

Author

Tauziède-Espariat, Arnault, Chotard, Guillaume, Le Loarer, François, Baud, Jessica, Azmani, Rihab, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Icher-De-Bouyn, Céline, Gimbert, Edouard, Hasty, Lauren, Métais, Alice, Chrétien, Fabrice, Varlet, Pascale, GHU Paris Psychiatrie et Neurosciences, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biopathologie (Institut Bergonié - CRLCC Bordeaux), UNICANCER-UNICANCER, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Département d'oncologie pédiatrique [CHU Bordeaux], Hôpital des Enfants - Groupe hospitalier Pellegrin - CHU de Bordeaux, CHU Bordeaux [Bordeaux], the RENOCLIP-LOC, and Martinez Rico, Clara

Subjects
Oncogene Proteins, Fusion, Brain Neoplasms, PATZ1, Kruppel-Like Transcription Factors, Nuclear Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Case Report, AFF2, N-Acetylglucosaminyltransferases, Neoplasms, Neuroepithelial, Neuroepithelial tumor, Repressor Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, Child, Preschool, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], LARGE1
Abstract

A novel DNA methylation class of tumor within the central nervous system, the "neuroepithelial tumor (NET), PATZ1 fusion-positive” has recently been identified in the literature, characterized by EWSR1- and MN1-PATZ1 fusions. The cellular origin of this tumor type remains unknown, wavering between glioneuronal or mesenchymal (as round cell sarcomas with EWSR1-PATZ1 of the soft tissue). Because of the low number of reported cases, this tumor type will not be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS). Herein, we report one case of a CNS tumor classified by DNA methylation analysis as NET-PATZ1 but harboring a novel LARGE1-AFF2 fusion which has until now never been described in soft tissue or the CNS. We compare its clinical, histopathological, immunophenotypical, and genetic features with those previously described in NET-PATZ1. Interestingly, the current case presented histopathological (astroblastoma-like features, glioneuronal phenotype), clinical (with a favorable course), genetic (1p loss), and epigenetic (DNA-methylation profiling) similarities to previously reported cases of NET-PATZ1. Our results added data suggesting that different histomolecular tumor subtypes seem to be included within the methylation class “NET, PATZ1 fusion-positive”, including non PATZ1 fusions, and that further cases are needed to better characterize them. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-022-01317-8.

Published
2021

6. Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1

Author

Sievers, Philipp, Sill, Martin, Blume, Christina, Tauziede-Espariat, Arnault, Schrimpf, Daniel, Stichel, Damian, Reuss, David E, Dogan, Helin, Hartmann, Christian, Mawrin, Christian, Hasselblatt, Martin, Stummer, Walter, Schick, Uta, Hench, Jürgen, Frank, Stephan, Ketter, Ralf, Schweizer, Leonille, Schittenhelm, Jens, Puget, Stéphanie, Brandner, Sebastian, Jaunmuktane, Zane, Küsters, Benno, Abdullaev, Zied, Pekmezci, Melike, Snuderl, Matija, Ratliff, Miriam, Herold-Mende, Christel, Unterberg, Andreas, Aldape, Kenneth, Ellison, David W, Wesseling, Pieter, Reifenberger, Guido, Wick, Wolfgang, Perry, Arie, Varlet, Pascale, Pfister, Stefan M, Jones, David TW, von Deimling, Andreas, Sahm, Felix, and German Consortium 'Aggressive Meningiomas'

Subjects
Male, German Consortium “Aggressive Meningiomas”, DNA Mutational Analysis, Clinical Sciences, DNA methylation profile, Cohort Studies, Young Adult, Rare Diseases, Genetic, otorhinolaryngologic diseases, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, Child, neoplasms, Clear cell, Cancer, Pediatric, Neurology & Neurosurgery, Brain Neoplasms, Human Genome, Neurosciences, Non-Histone, DNA, DNA Methylation, SMARCE1, Immunohistochemistry, nervous system diseases, Brain Disorders, Brain tumor, Chromosomal Proteins, DNA-Binding Proteins, Brain Cancer, Neoplasm Recurrence, Treatment Outcome, Local, Mutation, Disease Progression, Neoplasm, Female, Meningioma, Epigenesis, Genome-Wide Association Study
Abstract

Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.

Published
2021

7. Additional file 12 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 12. Copy number variation profile of case #8.

Published
2021
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8. Additional file 1 of The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of 'CNS tumors with BCOR internal tandem duplication'

Author

Tauziède-Espariat, Arnault, Pierron, Gaëlle, Siegfried, Aurore, Guillemot, Delphine, Uro-Coste, Emmanuelle, Nicaise, Yvan, Castel, David, Catalaa, Isabelle, Larrieu-Ciron, Delphine, Chaynes, Patrick, De Barros, Amaury, Nicolau, Julien, Gareton, Albane, Emmanuèle Lechapt, Chrétien, Fabrice, Bourdeaut, Franck, Doz, François, Bouchoucha, Yassine, Grill, Jacques, Kévin Beccaria, Boddaert, Nathalie, Saffroy, Raphaël, Pagès, Mélanie, and Varlet, Pascale

Abstract

Additional file 1: Table S1. Immunohistochemical findings of our cases of HGNET-BCOR with EP300:BCOR fusion.

Published
2021
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9. Additional file 8 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 8. Copy number variation profile of case #4.

Published
2021
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10. Additional file 14 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 14. Copy number variation profile of case #10.

Published
2021
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11. Additional file 17 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 17. Copy number variation profile of case #13.

Published
2021
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12. Additional file 7 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 7. Copy number variation profile of case #3.

Published
2021
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13. Additional file 11 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 11. Copy number variation profile of case #7.

Published
2021
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14. Additional file 10 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 10. Copy number variation profile of case #6.

Published
2021
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15. Additional file 6 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 6. Copy number variation profile of case #2.

Published
2021
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16. Additional file 15 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 15. Copy number variation profile of case #11.

Published
2021
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17. Additional file 16 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 16. Copy number variation profile of case #12.

Published
2021
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18. Additional file 5 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 5. Copy number variation profile of case #1.

Published
2021
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19. Additional file 13 of Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Tauziède-Espariat, Arnault, Siegfried, Aurore, Nicaise, Yvan, Kergrohen, Thomas, Sievers, Philipp, Vasiljevic, Alexandre, Roux, Alexandre, Dezamis, Edouard, Benevello, Chiara, Machet, Marie-Christine, Michalak, Sophie, Puiseux, Chloe, Llamas-Gutierrez, Francisco, Leblond, Pierre, Bourdeaut, Franck, Grill, Jacques, Dufour, Christelle, Guerrini-Rousseau, Léa, Abbou, Samuel, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Saffroy, Raphaël, Hasty, Lauren, Wahler, Ellen, Pagès, Mélanie, Andreiuolo, Felipe, Lechapt, Emmanuèle, Chrétien, Fabrice, Blauwblomme, Thomas, Beccaria, Kévin, Pallud, Johan, Puget, Stéphanie, Uro-Coste, Emmanuelle, and Varlet, Pascale

Abstract

Additional file 13. Copy number variation profile of case #9.

Published
2021
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20. Additional file 5 of Pediatric methylation class HGNET-MN1: unresolved issues with terminology and grading

Author

Tauziède-Espariat, Arnault, Pagès, Mélanie, Roux, Alexandre, Siegfried, Aurore, Uro-Coste, Emmanuelle, Nicaise, Yvan, Sevely, Annick, Gambart, Marion, Boetto, Sergio, Dupuy, Martin, Pomone Richard, Perbet, Romain, Vinchon, Matthieu, Caron, Sabine, Andreiuolo, Felipe, Gareton, Albane, Emmanuèle Lechapt, Chrétien, Fabrice, Puget, Stéphanie, Grill, Jacques, Boddaert, Nathalie, and Varlet, Pascale

Abstract

Additional file 5: Table S1. Immunoprofile of HGNET-MN1 of our series

Published
2020
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21. DNA methylation-based classification of central nervous system tumours

Author

Capper, David, Jones, David TW, Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E, Kratz, Annekathrin, Wefers, Annika K, Huang, Kristin, Pajtler, Kristian W, Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W, Lindenberg, Kerstin, Harter, Patrick N, Braczynski, Anne K, Plate, Karl H, Dohmen, Hildegard, Garvalov, Boyan K, Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J, Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R, Kohlhof, Patricia, Kristensen, Bjarne W, Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G, Driever, Pablo Hernáiz, Kramm, Christof M, Müller, Hermann L, Rutkowski, Stefan, von Hoff, Katja, Frühwald, Michael C, Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, and Jones, Chris

Subjects
Adult, Male, screening and diagnosis, Adolescent, General Science & Technology, Reproducibility of Results, Infant, and over, DNA Methylation, Middle Aged, Central Nervous System Neoplasms, Cohort Studies, Young Adult, Detection, 80 and over, Humans, Female, Child, Preschool, Aged, Unsupervised Machine Learning, 4.2 Evaluation of markers and technologies, Cancer
Abstract

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Published
2018

22. Additional file 5: of Transcriptomic and epigenetic profiling of ‘diffuse midline gliomas, H3 K27M-mutant’ discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location

Author

Castel, David, Philippe, Cathy, Kergrohen, Thomas, Sill, Martin, Merlevede, Jane, Barret, Emilie, Puget, Stéphanie, Sainte-Rose, Christian, Kramm, Christof, Jones, Chris, Varlet, Pascale, Pfister, Stefan, Grill, Jacques, Jones, David, and Marie-Anne Debily

Abstract

Figure S2. Principal component analysis of the GE profile of 21 DIPG using the gene associated with the highest standard deviation (n = 250 genes, H3.1-K27M DIPG in dark green and H3.3-K27M DIPG in light green). (PDF 54 kb)

Published
2018
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23. Additional file 3: of Transcriptomic and epigenetic profiling of ‘diffuse midline gliomas, H3 K27M-mutant’ discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location

Author

Castel, David, Philippe, Cathy, Kergrohen, Thomas, Sill, Martin, Merlevede, Jane, Barret, Emilie, Puget, Stéphanie, Sainte-Rose, Christian, Kramm, Christof, Jones, Chris, Varlet, Pascale, Pfister, Stefan, Grill, Jacques, Jones, David, and Marie-Anne Debily

Abstract

Figure S1. A. Principal component analysis of microarray GE profiling of 119 high grade gliomas as presented in Fig. 1b colored by mutational histone H3 status. Five pontine WT tumors that also harbor a H3K27 trimethylation loss by IHC are highlighted with red arrowheads. B- The gene expression data of the 120 genes associated with the highest standard deviation (n = 120 genes) were used for k-means analysis (k = 2) and the results represented in the same PCA as in panel A. The samples were color-coded according to k-means results, symbols reflect the histone H3 mutational status and their location are indicated in the plot. C-D. t-SNE analysis of the GE profiles of 119 pediatric high-grade gliomas using the genes associated with the highest standard deviation (n = 120 genes). The tumors were color-coded according to their location (A) or mutational histone H3 status (B) as described in Fig. 1. E- Overlapping of the gene lists resulting from differential analysis between: H3-K27M and wild-type tumors, H3-K27M and G34R tumors, H3-G34R and wild-type tumors, H3.1 K27M and H3.3-K27M tumors (adjusted p-value

Published
2018
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24. Additional file 6: of Transcriptomic and epigenetic profiling of ‘diffuse midline gliomas, H3 K27M-mutant’ discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location

Author

Castel, David, Philippe, Cathy, Kergrohen, Thomas, Sill, Martin, Merlevede, Jane, Barret, Emilie, Puget, Stéphanie, Sainte-Rose, Christian, Kramm, Christof, Jones, Chris, Varlet, Pascale, Pfister, Stefan, Grill, Jacques, Jones, David, and Marie-Anne Debily

Abstract

Figure S3. A-C. Metaplots showing average signal accumulation in reads of all the regions bound by H3K27me3 in at least one sample (A, n = 16,979) or H3K27me3 occupied regions with or without overlapping genes (B, n = 11,003 and C, n = 5976 respectively) in both H3.1- and H3.3-K27M GSC cells. Each plot is centered on the summit of the average occupancy and extended 10 kb upstream and downstream (− 10 kb and + 10 kb, respectively). Below the metaplots, heatmaps illustrating average H3K27me3 levels in the 20 kb genomic intervals centered on the summit of the peak in each subgroup are presented. D. Violin plot displaying transcript expression level of RNA-seq data in tpm in H3.1- and H3.3-K27M subgroups. Boxplots represent the 5th,25th,75th and 95th percentiles and the median of the transcript distribution, The distributions were divided in 4 categories: non expressed genes ( 10 tpm). (PDF 2819 kb)

Published
2018
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25. Automatic quantification of the microvascular density on whole slide images, applied to paediatric brain tumours

Author

Deroulers, Christophe, Dangouloff-Ros, Volodia, Badoual, Mathilde, Varlet, Pascale, and Boddaert, Nathalie

Subjects
lcsh:R5-920, lcsh:Medical technology, Image Processing, Digital Pathology, Quantitative Biology - Tissues and Organs, Brain Tumour, lcsh:Computer applications to medicine. Medical informatics, lcsh:R855-855.5, FOS: Biological sciences, Microvessels, Whole Slide Images, lcsh:R858-859.7, Angiogenesis, lcsh:Medicine (General), Tissues and Organs (q-bio.TO)
Abstract

Background Angiogenesis is a key phenomenon for tumour progression, diagnosis and treatment in brain tumours and more generally in oncology. Presently, its precise, direct quantitative assessment can only be done on whole tissue sections immunostained to reveal vascular endothelial cells. But this is a tremendous task for the pathologist and a challenge for the computer since digitised whole tissue sections, whole slide mages (WSI), contain typically around ten gigapixels. Methods We define and implement an algorithm that determines automatically, on a WSI at objective magnification 40x, the regions of tissue, the regions without blur and the regions of large puddles of red blood cells, and constructs the mask of blur-free, significant tissue on the WSI. Then it calibrates automatically the optical density ratios of the immunostaining of the vessel walls and of the counterstaining, performs a colour deconvolution inside the regions of blur-free tissue, and finds the vessel walls inside these regions by selecting, on the image resulting from the colour deconvolution, zones which satisfy a double-threshold criterion. The two thresholds involved are automatically computed from the WSI so as to cope with variations in staining and digitisation parameters. A mask of vessel wall regions on the WSI is produced. The density of microvessels is finally computed as the fraction of the area of significant tissue which is occupied by vessel walls. We apply this algorithm to a set of 186 WSI of paediatric brain tumours from World Health Organisation grades I to IV. Results The algorithm and its implementation are able to distinguish on the WSI the significant tissue and the vessel walls. The segmentations are of very good quality although the set of slides is very heterogeneous (in tumour type, in staining and digitisation parameters, and inside WSI themselves, where the tissue was often very fragmented). The computation time is of the order of a fraction of an hour for each WSI even though a modest desktop computer is used (a 2012 Mac mini) and the average size of WSI is 7 gigapixels. The computed microvascular density is found to be robust. We find that it strongly correlates with the tumour grade. Conclusions We have introduced a method of automatic segmentation of significant, blur-free tissue and of vessel walls, and of quantification of the density of microvessels, in WSI. We successfully tested it on a large variety of brain tumour tissue samples. This method requires no training and estimates automatically several important parameters of the segmentation. It is robust and can easily be applied to other tumour types and other stainings. It should improve the reproducibility of quantitative estimates in pathology while sparing the pathologist time and effort.

Published
2017
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26. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

Author

Sturm, Dominik, Orr, Brent A, Toprak, Umut H, Hovestadt, Volker, Jones, David TW, Capper, David, Sill, Martin, Buchhalter, Ivo, Northcott, Paul A, Leis, Irina, Ryzhova, Marina, Koelsche, Christian, Pfaff, Elke, Allen, Sariah J, Balasubramanian, Gnanaprakash, Worst, Barbara C, Pajtler, Kristian W, Brabetz, Sebastian, Johann, Pascal D, Sahm, Felix, Reimand, Jüri, Mackay, Alan, Carvalho, Diana M, Remke, Marc, Phillips, Joanna J, Perry, Arie, Cowdrey, Cynthia, Drissi, Rachid, Fouladi, Maryam, Giangaspero, Felice, Łastowska, Maria, Grajkowska, Wiesława, Scheurlen, Wolfram, Pietsch, Torsten, Hagel, Christian, Gojo, Johannes, Lötsch, Daniela, Berger, Walter, Slavc, Irene, Haberler, Christine, Jouvet, Anne, Holm, Stefan, Hofer, Silvia, Prinz, Marco, Keohane, Catherine, Fried, Iris, Mawrin, Christian, Scheie, David, Mobley, Bret C, Schniederjan, Matthew J, Santi, Mariarita, Buccoliero, Anna M, Dahiya, Sonika, Kramm, Christof M, von Bueren, André O, von Hoff, Katja, Rutkowski, Stefan, Herold-Mende, Christel, Frühwald, Michael C, Milde, Till, Hasselblatt, Martin, Wesseling, Pieter, Rößler, Jochen, Schüller, Ulrich, Ebinger, Martin, Schittenhelm, Jens, Frank, Stephan, Grobholz, Rainer, Vajtai, Istvan, Hans, Volkmar, Schneppenheim, Reinhard, Zitterbart, Karel, Collins, V Peter, Aronica, Eleonora, Varlet, Pascale, Puget, Stephanie, Dufour, Christelle, Grill, Jacques, Figarella-Branger, Dominique, Wolter, Marietta, Schuhmann, Martin U, Shalaby, Tarek, Grotzer, Michael, van Meter, Timothy, Monoranu, Camelia-Maria, Felsberg, Jörg, Reifenberger, Guido, Snuderl, Matija, Forrester, Lynn Ann, Koster, Jan, Versteeg, Rogier, Volckmann, Richard, van Sluis, Peter, Wolf, Stephan, Mikkelsen, Tom, Gajjar, Amar, Aldape, Kenneth, Moore, Andrew S, Taylor, Michael D, and Jones, Chris

Subjects
Pediatric Research Initiative, Pediatric Cancer, Molecular Sequence Data, Neuroectodermal Tumors, Medical and Health Sciences, Central Nervous System Neoplasms, Neuroblastoma, Rare Diseases, Proto-Oncogene Proteins, Humans, Amino Acid Sequence, Child, Cancer, Pediatric, Neoplastic, Tumor Suppressor Proteins, Gene Expression Profiling, Neurosciences, Forkhead Transcription Factors, DNA Methylation, Biological Sciences, Brain Disorders, Repressor Proteins, Brain Cancer, Orphan Drug, Gene Expression Regulation, Trans-Activators, Signal Transduction, Developmental Biology
Abstract

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

Published
2016

27. HGG-03. INTEGRATED MOLECULAR AND PATHOLOGICAL CHARACTERISATION OF NON-BRAINSTEM PAEDIATRIC HIGH GRADE GLIOMA FROM THE HERBY PHASE II RANDOMISED TRIAL

Author

Mackay, Alan, Burford, Anna, Molinari, Valeria, Jones, David, Rodriguez, Daniel, Morgan, Paul, Pfister, Stefan, Wurdinger, Thomas, Tam, Rachel, das Thakur, Meghna, Garcia, Josep, Vassal, Gilles, Grill, Jacques, Jaspan, Tim, Varlet, Pascale, and Jones, Chris

Subjects
Abstracts, Cancer Research, Oncology, Neurology (clinical)
Abstract

The HERBY trial was a phase-II open-label, randomised, multicentre trial evaluating bevacizumab in patients with newly-diagnosed non-brainstem high grade glioma (HGG) between the ages of 3-18yrs. 121 patients were randomised with 1yr event-free survival as the primary end-point. Confirmation of HGG diagnosis by reference pathology was mandatory before randomisation, followed by review with five independent expert neuropathologists. We collected specimens from 89 patients consenting to translational research, and performed Sanger sequencing for H3F3A, Illumina 450K BeadArray methylation profiling, and whole exome sequencing and RNA sequencing where possible. 7/89 patients (8%) harboured H3F3A G34R/V mutations, whilst 24/89 (27%) harboured H3F3A K27M, the latter reflecting a high proportion of the novel entity recognised in the 2016 WHO classification of diffuse midline glioma with H3K27M mutation. Both histone mutations conferred a significantly shorter progression-free (p=0.0104) and overall survival (p=0.00159). 450K methylation subtyping additionally identified a number of subgroups in histone wild-type cases. These included infrequent (4/86, 4.6%) cases with IDH1 mutation in older children, further categorised into astrocytic ATRX-mutant (n=3) or 1p19q co-deleted with TERT promoter mutation (n=1). 9/74, (12%) of cases were classified as biologically resembling pleomorphic xanthoastrocytoma (PXA) by methylation profiling, with 5/9 harbouring BRAF V600E mutations and epithelioid histology, and 3/9 NF1 mutation and giant cell features. Three cases had methylation profiles more closely resembling low grade gliomas, though were morphologically high grade, and harboured MAPK dysregulation in two cases, with the third part of an additional infant (

Published
2017

28. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort

Author

Waszak, Sebastian M, Northcott, Paul A, Buchhalter, Ivo, Robinson, Giles W, Sutter, Christian, Groebner, Susanne, Grund, Kerstin B, Brugières, Laurence, Jones, David TW, Pajtler, Kristian W, Morrissy, A Sorana, Kool, Marcel, Sturm, Dominik, Chavez, Lukas, Ernst, Aurelie, Brabetz, Sebastian, Hain, Michael, Zichner, Thomas, Segura-Wang, Maia, Weischenfeldt, Joachim, Rausch, Tobias, Mardin, Balca R, Zhou, Xin, Baciu, Cristina, Lawerenz, Christian, Chan, Jennifer A, Varlet, Pascale, Guerrini-Rousseau, Lea, Fults, Daniel W, Grajkowska, Wiesława, Hauser, Peter, Jabado, Nada, Ra, Young-Shin, Zitterbart, Karel, Shringarpure, Suyash S, De La Vega, Francisco M, Bustamante, Carlos D, Ng, Ho-Keung, Perry, Arie, MacDonald, Tobey J, Hernáiz Driever, Pablo, Bendel, Anne E, Bowers, Daniel C, McCowage, Geoffrey, Chintagumpala, Murali M, Cohn, Richard, Hassall, Timothy, Fleischhack, Gudrun, Eggen, Tone, Wesenberg, Finn, Feychting, Maria, Lannering, Birgitta, Schüz, Joachim, Johansen, Christoffer, Andersen, Tina V, Röösli, Martin, Kuehni, Claudia E, Grotzer, Michael, Kjaerheim, Kristina, Monoranu, Camelia M, Archer, Tenley C, Duke, Elizabeth, Pomeroy, Scott L, Shelagh, Redmond, Frank, Stephan, Sumerauer, David, Scheurlen, Wolfram, Ryzhova, Marina V, Milde, Till, Kratz, Christian P, Samuel, David, Zhang, Jinghui, Solomon, David A, Marra, Marco, Eils, Roland, Bartram, Claus R, Von Hoff, Katja, Rutkowski, Stefan, Ramaswamy, Vijay, Gilbertson, Richard J, Korshunov, Andrey, Taylor, Michael D, Lichter, Peter, Malkin, David, Gajjar, Amar, Korbel, Jan O, and Pfister, Stefan M

Subjects
Adult, Male, Heredity, Adolescent, DNA Mutational Analysis, Young Adult, Predictive Value of Tests, Risk Factors, Exome Sequencing, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Genetic Testing, Prospective Studies, Cerebellar Neoplasms, Child, Germ-Line Mutation, Retrospective Studies, Models, Genetic, Gene Expression Profiling, Infant, Reproducibility of Results, DNA Methylation, Progression-Free Survival, 3. Good health, Pedigree, Phenotype, Child, Preschool, Female, Transcriptome, Medulloblastoma
Abstract

BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

29. The molecular landscape of glioma in patients with Neurofibromatosis 1

Author

Dominique Vidaud, Mariona Suñol, Tala, Francesco DiMeco, John de Groot, Gaetano Finocchiaro, Fulvio D'Angelo, Luc Bauchet, Marica Eoli, Véronique Lorgis, David Meyronet, Kristin Alfaro, Luciano Garofano, John M. Slopis, Laurent Capelle, Pascale Varlet, Giulia Berzero, Mario Cangiano, Veronica Saletti, Romuald Seizeur, Jing Zhang, Carlo Efisio Marras, Veronique Frattini, Walid Farah, Cinzia Lavarino, David Cachia, Genevieve Lewis, Michele Ceccarelli, Seung-Ki Kim, David E. Reuss, Hugues Loiseau, Carlos Kamiya-Matsuoka, Do-Hyun Nam, Krishna P. Bhat, Stéphane Goutagny, Karima Mokhtari, François Ducray, Anna Lasorella, Colin Watts, Francesca Pia Caruso, Hector Salvador, Antonio Iavarone, F. Vandenbos, Ian E. McCutcheon, Susanna Ronchi, Viviane Tabar, Marc Sanson, D'Angelo, Fulvio, Ceccarelli, Michele, Tala, Garofano, Luciano, Zhang, Jing, Frattini, Veronique, Caruso, Francesca P., Lewis, Genevieve, Alfaro, Kristin D., Bauchet, Luc, Berzero, Giulia, Cachia, David, Cangiano, Mario, Capelle, Laurent, de Groot, John, Dimeco, Francesco, Ducray, Francoi, Farah, Walid, Finocchiaro, Gaetano, Goutagny, Stephane, Kamiya-Matsuoka, Carlo, Lavarino, Cinzia, Loiseau, Hugue, Lorgis, Veronique, Marras, Carlo E., Mccutcheon, Ian, Nam, Do-Hyun, Ronchi, Susanna, Saletti, Veronica, Seizeur, Romuald, Slopis, John, Sunol, Mariona, Vandenbos, Fanny, Varlet, Pascale, Vidaud, Dominique, Watts, Colin, Tabar, Viviane, Reuss, David E., Kim, Seung-Ki, Meyronet, David, Mokhtari, Karima, Salvador, Hector, Bhat, Krishna P., Eoli, Marica, Sanson, Marc, Lasorella, Anna, Iavarone, Antonio, D'Angelo, F., Ceccarelli, M., Garofano, L., Zhang, J., Frattini, V., Caruso, F. P., Lewis, G., Alfaro, K. D., Bauchet, L., Berzero, G., Cachia, D., Cangiano, M., Capelle, L., de Groot, J., Dimeco, F., Ducray, F., Farah, W., Finocchiaro, G., Goutagny, S., Kamiya-Matsuoka, C., Lavarino, C., Loiseau, H., Lorgis, V., Marras, C. E., Mccutcheon, I., Nam, D. -H., Ronchi, S., Saletti, V., Seizeur, R., Slopis, J., Sunol, M., Vandenbos, F., Varlet, P., Vidaud, D., Watts, C., Tabar, V., Reuss, D. E., Kim, S. -K., Meyronet, D., Mokhtari, K., Salvador, H., Bhat, K. P., Eoli, M., Sanson, M., Lasorella, A., Iavarone, A., Columbia University Medical Center (CUMC), Columbia University [New York], University of Sannio [Benevento], The University of Texas M.D. Anderson Cancer Center [Houston], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Medical University of South Carolina [Charleston] (MUSC), Service de Neurochirurgie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Milan, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Sungkyunkwan University [Suwon] (SKKU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Pasteur [Nice] (CHU), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Sainte Anne [Paris], Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], University of Birmingham [Birmingham], Memorial Sloane Kettering Cancer Center [New York], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Heidelberg University, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), and CHU Cochin [AP-HP]

Subjects
0301 basic medicine, Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, X-linked Nuclear Protein, Neurofibromatosis 1, Adolescent, [SDV]Life Sciences [q-bio], T-Lymphocytes, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Germline mutation, CDKN2A, Antigens, Neoplasm, Glioma, medicine, Humans, Epigenetics, Neurofibromatosis, 10. No inequality, Child, Gene, neoplasms, ATRX, Germ-Line Mutation, Cancer, Neurofibromin 1, Brain Neoplasms, Reproducibility of Results, General Medicine, DNA Methylation, Middle Aged, medicine.disease, 3. Good health, nervous system diseases, 030104 developmental biology, 030220 oncology & carcinogenesis, Child, Preschool, DNA methylation, Cancer research, Genomics, Bioinformatic, Female, Transcriptome
Abstract

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.

Published
2018

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