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179 results on '"Ambros, Peter F"'

2. Deep SNP: An End-to-end Deep Neural Network with Attention-based Localization for Break-point Detection in SNP Array Genomic data

Author

Eghbal-zadeh, Hamid, Fischer, Lukas, Popitsch, Niko, Kromp, Florian, Taschner-Mandl, Sabine, Koutini, Khaled, Gerber, Teresa, Bozsaky, Eva, Ambros, Peter F., Ambros, Inge M., Widmer, Gerhard, and Moser, Bernhard A.

Subjects
Quantitative Biology - Genomics, Computer Science - Machine Learning
Abstract

Diagnosis and risk stratification of cancer and many other diseases require the detection of genomic breakpoints as a prerequisite of calling copy number alterations (CNA). This, however, is still challenging and requires time-consuming manual curation. As deep-learning methods outperformed classical state-of-the-art algorithms in various domains and have also been successfully applied to life science problems including medicine and biology, we here propose Deep SNP, a novel Deep Neural Network to learn from genomic data. Specifically, we used a manually curated dataset from 12 genomic single nucleotide polymorphism array (SNPa) profiles as truth-set and aimed at predicting the presence or absence of genomic breakpoints, an indicator of structural chromosomal variations, in windows of 40,000 probes. We compare our results with well-known neural network models as well as Rawcopy though this tool is designed to predict breakpoints and in addition genomic segments with high sensitivity. We show, that Deep SNP is capable of successfully predicting the presence or absence of a breakpoint in large genomic windows and outperforms state-of-the-art neural network models. Qualitative examples suggest that integration of a localization unit may enable breakpoint detection and prediction of genomic segments, even if the breakpoint coordinates were not provided for network training. These results warrant further evaluation of DeepSNP for breakpoint localization and subsequent calling of genomic segments., Comment: Accepted at the Joint ICML and IJCAI 2018 Workshop on Computational Biology

Published
2018

3. Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup

Author

Martinez-Monleon, Angela, Kryh Öberg, Hanna, Gaarder, Jennie, Berbegall, Ana P., Javanmardi, Niloufar, Djos, Anna, Ussowicz, Marek, Taschner-Mandl, Sabine, Ambros, Inge M., Øra, Ingrid, Sandstedt, Bengt, Beiske, Klaus, Ladenstein, Ruth, Noguera, Rosa, Ambros, Peter F., Gordon Murkes, Lena, Ljungman, Gustaf, Kogner, Per, Fransson, Susanne, and Martinsson, Tommy

Published
2022
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5. Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project

Author

Thompson, Daria, Vo, Kieuhoa T, London, Wendy B, Fischer, Matthias, Ambros, Peter F, Nakagawara, Akira, Brodeur, Garrett M, Matthay, Katherine K, and DuBois, Steven G

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Neuroblastoma, Neurosciences, Rare Diseases, Pediatric, Genetics, Cancer, Age Factors, Chromosome Aberrations, Female, Gene Amplification, Humans, Infant, Logistic Models, Loss of Heterozygosity, Male, N-Myc Proto-Oncogene Protein, Neoplasm Grading, Neoplasm Staging, Nuclear Proteins, Oncogene Proteins, Predictive Value of Tests, Prognosis, decision trees, gene amplification, neuroblastoma, genetics, oncogene proteins, neuroblastoma/genetics, oncogene proteins/genetics, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Public health
Abstract

BackgroundMYCN gene amplification (MNA) is a hallmark of aggressive neuroblastoma. This study was performed to determine univariate and multivariate predictors of tumor MNA.MethodsData from the International Neuroblastoma Risk Group were analyzed for a subset of 7102 patients with known MYCN status. Chi-square testing and logistic regression were used to identify univariate and multivariate predictors of MYCN status. Recursive partitioning was used to identify groups of patients with maximal differences in rates of MNA.ResultsAll clinical features (age ≥ 18 months, high ferritin levels, high lactate dehydrogenase [LDH] levels, International Neuroblastoma Staging System stage 4, and adrenal sites) and pathological/biological features (DNA index ≤ 1, high mitosis-karyorrhexis index [MKI], undifferentiated/poorly differentiated grade, unfavorable histology according to the International Neuroblastoma Pathology Classification, and segmental chromosomal aberrations [SCAs]) were significantly associated with MNA. LDH (odds ratio [OR], 8.4; P < .001) and chromosomal 1p loss of heterozygosity (OR, 19.8; P < .001) were the clinical and biological variables, respectively, most strongly associated with MNA. In logistic regression, all variables except chromosome 17q aberration and pooled SCAs were independently predictive of MNA. Recursive partitioning identified subgroups with disparate rates of MNA, including subgroups with 85.7% MNA (patients with high LDH levels who had poorly differentiated adrenal tumors with chromosome 1p deletion) and 0.6% MNA (localized tumors having hyperdiploidy and low MKIs and lacking chromosome 1p aberrations).ConclusionsMNA is strongly associated with other clinical and biological variables in neuroblastoma. Recursive partitioning has identified subgroups of neuroblastoma patients with highly disparate rates of MNA. These findings can be used to inform investigations of molecular mechanisms of MNA.

Published
2016

6. Advances in Risk Classification and Treatment Strategies for Neuroblastoma

Author

Pinto, Navin R, Applebaum, Mark A, Volchenboum, Samuel L, Matthay, Katherine K, London, Wendy B, Ambros, Peter F, Nakagawara, Akira, Berthold, Frank, Schleiermacher, Gudrun, Park, Julie R, Valteau-Couanet, Dominique, Pearson, Andrew DJ, and Cohn, Susan L

Subjects
Cancer, Pediatric Cancer, Neuroblastoma, Pediatric, Orphan Drug, Rare Diseases, Neurosciences, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, Adolescent, Age of Onset, Child, Child, Preschool, Cooperative Behavior, Diffusion of Innovation, Humans, Infant, Infant, Newborn, Interdisciplinary Communication, International Cooperation, Medical Oncology, Pediatrics, Predictive Value of Tests, Risk Assessment, Risk Factors, Survivors, Time Factors, Treatment Outcome, Young Adult, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations.

Published
2015

8. Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions

Author

Schmelz, Karin, Toedling, Joern, Huska, Matt, Cwikla, Maja C., Kruetzfeldt, Louisa-Marie, Proba, Jutta, Ambros, Peter F., Ambros, Inge M., Boral, Sengül, Lodrini, Marco, Chen, Celine Y., Burkert, Martin, Guergen, Dennis, Szymansky, Annabell, Astrahantseff, Kathy, Kuenkele, Annette, Haase, Kerstin, Fischer, Matthias, Deubzer, Hedwig E., Hertwig, Falk, Hundsdoerfer, Patrick, Henssen, Anton G., Schwarz, Roland F., Schulte, Johannes H., and Eggert, Angelika

Published
2021
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9. Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden

Author

Peneder, Peter, Stütz, Adrian M., Surdez, Didier, Krumbholz, Manuela, Semper, Sabine, Chicard, Mathieu, Sheffield, Nathan C., Pierron, Gaelle, Lapouble, Eve, Tötzl, Marcus, Ergüner, Bekir, Barreca, Daniele, Rendeiro, André F., Agaimy, Abbas, Boztug, Heidrun, Engstler, Gernot, Dworzak, Michael, Bernkopf, Marie, Taschner-Mandl, Sabine, Ambros, Inge M., Myklebost, Ola, Marec-Bérard, Perrine, Burchill, Susan Ann, Brennan, Bernadette, Strauss, Sandra J., Whelan, Jeremy, Schleiermacher, Gudrun, Schaefer, Christiane, Dirksen, Uta, Hutter, Caroline, Boye, Kjetil, Ambros, Peter F., Delattre, Olivier, Metzler, Markus, Bock, Christoph, and Tomazou, Eleni M.

Published
2021
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10. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial

Author

Ladenstein, Ruth, Pötschger, Ulrike, Pearson, Andrew D J, Brock, Penelope, Luksch, Roberto, Castel, Victoria, Yaniv, Isaac, Papadakis, Vassilios, Laureys, Geneviève, Malis, Josef, Balwierz, Walentyna, Ruud, Ellen, Kogner, Per, Schroeder, Henrik, de Lacerda, Ana Forjaz, Beck-Popovic, Maja, Bician, Pavel, Garami, Miklós, Trahair, Toby, Canete, Adela, Ambros, Peter F, Holmes, Keith, Gaze, Mark, Schreier, Günter, Garaventa, Alberto, Vassal, Gilles, Michon, Jean, and Valteau-Couanet, Dominique

Published
2017
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12. Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study

Author

Berbegall, Ana P., Bogen, Dominik, Pötschger, Ulrike, Beiske, Klaus, Bown, Nick, Combaret, Valérie, Defferrari, Raffaella, Jeison, Marta, Mazzocco, Katia, Varesio, Luigi, Vicha, Ales, Ash, Shifra, Castel, Victoria, Coze, Carole, Ladenstein, Ruth, Owens, Cormac, Papadakis, Vassilios, Ruud, Ellen, Amann, Gabriele, Sementa, Angela R., Navarro, Samuel, Ambros, Peter F., Noguera, Rosa, and Ambros, Inge M.

Published
2018
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13. Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial

Author

Flaadt, Tim, primary, Ladenstein, Ruth L., additional, Ebinger, Martin, additional, Lode, Holger N., additional, Arnardóttir, Helga Björk, additional, Poetschger, Ulrike, additional, Schwinger, Wolfgang, additional, Meisel, Roland, additional, Schuster, Friedhelm R., additional, Döring, Michaela, additional, Ambros, Peter F., additional, Queudeville, Manon, additional, Fuchs, Jörg, additional, Warmann, Steven W., additional, Schäfer, Jürgen, additional, Seitz, Christian, additional, Schlegel, Patrick, additional, Brecht, Ines B., additional, Holzer, Ursula, additional, Feuchtinger, Tobias, additional, Simon, Thorsten, additional, Schulte, Johannes H., additional, Eggert, Angelika, additional, Teltschik, Heiko-Manuel, additional, Illhardt, Toni, additional, Handgretinger, Rupert, additional, and Lang, Peter, additional

Published
2023
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14. Supplementary Table S6 from Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Author

Abbasi, M. Reza, primary, Rifatbegovic, Fikret, primary, Brunner, Clemens, primary, Mann, Georg, primary, Ziegler, Andrea, primary, Pötschger, Ulrike, primary, Crazzolara, Roman, primary, Ussowicz, Marek, primary, Benesch, Martin, primary, Ebetsberger-Dachs, Georg, primary, Chan, Godfrey C.F., primary, Jones, Neil, primary, Ladenstein, Ruth, primary, Ambros, Inge M., primary, and Ambros, Peter F., primary

Published
2023
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15. Supplementary Figures S1-S8 from Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Author

Abbasi, M. Reza, primary, Rifatbegovic, Fikret, primary, Brunner, Clemens, primary, Mann, Georg, primary, Ziegler, Andrea, primary, Pötschger, Ulrike, primary, Crazzolara, Roman, primary, Ussowicz, Marek, primary, Benesch, Martin, primary, Ebetsberger-Dachs, Georg, primary, Chan, Godfrey C.F., primary, Jones, Neil, primary, Ladenstein, Ruth, primary, Ambros, Inge M., primary, and Ambros, Peter F., primary

Published
2023
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17. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma

Author

Sheffield, Nathan C, Pierron, Gaelle, Klughammer, Johanna, Datlinger, Paul, Schönegger, Andreas, Schuster, Michael, Hadler, Johanna, Surdez, Didier, Guillemot, Delphine, Lapouble, Eve, Freneaux, Paul, Champigneulle, Jacqueline, Bouvier, Raymonde, Walder, Diana, Ambros, Ingeborg M, Hutter, Caroline, Sorz, Eva, Amaral, Ana T, de Álava, Enrique, Schallmoser, Katharina, Strunk, Dirk, Rinner, Beate, Liegl-Atzwanger, Bernadette, Huppertz, Berthold, Leithner, Andreas, de Pinieux, Gonzague, Terrier, Philippe, Laurence, Valérie, Michon, Jean, Ladenstein, Ruth, Holter, Wolfgang, Windhager, Reinhard, Dirksen, Uta, Ambros, Peter F, Delattre, Olivier, Kovar, Heinrich, Bock, Christoph, and Tomazou, Eleni M

Subjects
Genetic aspects, Health aspects, Methylation -- Health aspects, Cancer cells -- Genetic aspects, Ewing's sarcoma -- Genetic aspects
Abstract

Author(s): Nathan C Sheffield [1]; Gaelle Pierron [2]; Johanna Klughammer [1]; Paul Datlinger [1]; Andreas Schönegger [1]; Michael Schuster [1]; Johanna Hadler [1]; Didier Surdez [3]; Delphine Guillemot [2]; Eve [...], Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.

Published
2017
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20. Human repair‐related Schwann cells adopt functions of antigen‐presenting cells in vitro

Author

Berner, Jakob, primary, Weiss, Tamara, additional, Sorger, Helena, additional, Rifatbegovic, Fikret, additional, Kauer, Max, additional, Windhager, Reinhard, additional, Dohnal, Alexander, additional, Ambros, Peter F., additional, Ambros, Inge M., additional, Boztug, Kaan, additional, Steinberger, Peter, additional, and Taschner‐Mandl, Sabine, additional

Published
2022
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21. Abstract 977: Mapping bone marrow metastasis in neuroblastoma by deep multiplex imaging and transcriptomics

Author

Lazic, Daria, primary, Kromp, Florian, additional, Rifatbegovic, Fikret, additional, Repiscak, Peter, additional, Mivalt, Filip, additional, Halbritter, Florian, additional, Bernkopf, Marie, additional, Bileck, Andrea, additional, Ussowicz, Marek, additional, Ambros, Inge M., additional, Ambros, Peter F., additional, Gerner, Christopher, additional, Ladenstein, Ruth, additional, Ostalecki, Christian, additional, and Taschner-Mandl, Sabine, additional

Published
2022
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23. VP2: Schwann Cells Regulate Neuronal Differentiation by Epidermal Growth Factor-Like Protein 8

Author

Weiss, Tamara, primary, Taschner-Mandl, Sabine, additional, Janker, Lukas, additional, Bileck, Andrea, additional, Rifatbegovic, Fikret, additional, Kromp, Florian, additional, Sorger, Helena, additional, Kauer, Maximilian O., additional, Frech, Christian, additional, Windhager, Reinhard, additional, Gerner, Christopher, additional, Ambros, Peter F., additional, and Ambros, Inge M., additional

Published
2022
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24. Landscape of Bone Marrow Metastasis in Human Neuroblastoma Unraveled by Transcriptomics and Deep Multiplex Imaging

Author

Lazic, Daria, Kromp, Florian, Rifatbegovic, Fikret, Repiscak, Peter, Kirr, Michael, Mivalt, Filip, Halbritter, Florian, Bernkopf, Marie, Bileck, Andrea, Ussowicz, Marek, Ambros, Inge M., Ambros, Peter F., Gerner, Christopher, Ladenstein, Ruth, Ostalecki, Christian, and Taschner-Mandl, Sabine

Subjects
multiplex imaging, bone marrow, disseminated tumor cells, deep learning, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Article, transcriptomics, neuroblastoma, sngle-cell analysis, tumor heterogeneity, metastasis, tumor microenvironment, single-cell analysis, ddc:610, RC254-282, metastatis
Abstract

Simple Summary Bone marrow metastasis frequently occurs in patients with solid cancers and most often leads to poor outcome. Yet, the composition of bone marrow metastases, including tumor and surrounding cells, has so far not been characterized. Herein, we aimed to investigate the diversity of tumor and surrounding cells, i.e., the microenvironment, in bone marrow metastases, using the childhood tumor neuroblastoma as a model. To this end, we screened genome-wide datasets to define a panel of cell-specific markers for multiplex microscopy of metastatic bone marrow samples, and developed DeepFLEX, a computational pipeline for subsequent image analysis. Thereby, we identified 35,000 single cells covering metastasized tumor cells, and various types of developing immune and bone marrow cells. In parallel, we analyzed the transcriptome, i.e., all genes that are expressed as mRNA, of 38 patients with and without bone marrow metastasis. We found vast tumor cell diversity and identified a marker protein, FAIM2, which can help to identify a broader range of tumor cell variants. In addition we showed that tumor cell metastasis in the bone marrow is associated with an immune response resembling inflammation, and the presence of cells that can repress an immune attack against cancer cells. Our study suggests that metastatic tumor cells are shaping the bone marrow microenvironment and builds the basis to further investigate its clinical relevance. Abstract While the bone marrow attracts tumor cells in many solid cancers leading to poor outcome in affected patients, comprehensive analyses of bone marrow metastases have not been performed on a single-cell level. We here set out to capture tumor heterogeneity and unravel microenvironmental changes in neuroblastoma, a solid cancer with bone marrow involvement. To this end, we employed a multi-omics data mining approach to define a multiplex imaging panel and developed DeepFLEX, a pipeline for subsequent multiplex image analysis, whereby we constructed a single-cell atlas of over 35,000 disseminated tumor cells (DTCs) and cells of their microenvironment in the metastatic bone marrow niche. Further, we independently profiled the transcriptome of a cohort of 38 patients with and without bone marrow metastasis. Our results revealed vast diversity among DTCs and suggest that FAIM2 can act as a complementary marker to capture DTC heterogeneity. Importantly, we demonstrate that malignant bone marrow infiltration is associated with an inflammatory response and at the same time the presence of immuno-suppressive cell types, most prominently an immature neutrophil/granulocytic myeloid-derived suppressor-like cell type. The presented findings indicate that metastatic tumor cells shape the bone marrow microenvironment, warranting deeper investigations of spatio-temporal dynamics at the single-cell level and their clinical relevance.

Published
2021

25. Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Author

Bellini, Angela, primary, Pötschger, Ulrike, additional, Bernard, Virginie, additional, Lapouble, Eve, additional, Baulande, Sylvain, additional, Ambros, Peter F., additional, Auger, Nathalie, additional, Beiske, Klaus, additional, Bernkopf, Marie, additional, Betts, David R., additional, Bhalshankar, Jaydutt, additional, Bown, Nick, additional, de Preter, Katleen, additional, Clément, Nathalie, additional, Combaret, Valérie, additional, Font de Mora, Jaime, additional, George, Sally L., additional, Jiménez, Irene, additional, Jeison, Marta, additional, Marques, Barbara, additional, Martinsson, Tommy, additional, Mazzocco, Katia, additional, Morini, Martina, additional, Mühlethaler-Mottet, Annick, additional, Noguera, Rosa, additional, Pierron, Gaelle, additional, Rossing, Maria, additional, Taschner-Mandl, Sabine, additional, Van Roy, Nadine, additional, Vicha, Ales, additional, Chesler, Louis, additional, Balwierz, Walentyna, additional, Castel, Victoria, additional, Elliott, Martin, additional, Kogner, Per, additional, Laureys, Geneviève, additional, Luksch, Roberto, additional, Malis, Josef, additional, Popovic-Beck, Maja, additional, Ash, Shifra, additional, Delattre, Olivier, additional, Valteau-Couanet, Dominique, additional, Tweddle, Deborah A., additional, Ladenstein, Ruth, additional, and Schleiermacher, Gudrun, additional

Published
2021
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28. Frequency and prognostic impact of alk amplifications and mutations in the european neuroblastoma study group (siopen) high-risk neuroblastoma trial (hr-nbl1)

Author

Bellini, Angela, Potschger, Ulrike, Bernard, Virginie, Lapouble, Eve, Baulande, Sylvain, Ambros, Peter F., Auger, Nathalie, Beiske, Klaus, Bernkopf, Marie, Betts, David R., Bhalshankar, Jaydutt, Bown, Nick, De Preter, Katleen, Clement, Nathalie, Combaret, Valerie, De Mora, Jaime Font, George, Sally L., Jimenez, Irene, Jeison, Marta, Marques, Barbara, Martinsson, Tommy, Mazzocco, Katia, Morini, Martina, Muhlethaler-Mottet, Annick, Noguera, Rosa, Pierron, Gaelle, Rossing, Maria, Taschner-Mandl, Sabine, Van Roy, Nadine, Vicha, Ales, Chesler, Louis, Balwierz, Walentyna, Castel, Victoria, Elliott, Martin, Kogner, Per, Laureys, Genevieve, Luksch, Roberto, Malis, Josef, Popovic-Beck, Maja, Ash, Shifra, Delattre, Olivier, Valteau-Couanet, Dominique, Tweddle, Deborah A., Ladenstein, Ruth, Schleiermacher, Gudrun, Bellini, Angela, Potschger, Ulrike, Bernard, Virginie, Lapouble, Eve, Baulande, Sylvain, Ambros, Peter F., Auger, Nathalie, Beiske, Klaus, Bernkopf, Marie, Betts, David R., Bhalshankar, Jaydutt, Bown, Nick, De Preter, Katleen, Clement, Nathalie, Combaret, Valerie, De Mora, Jaime Font, George, Sally L., Jimenez, Irene, Jeison, Marta, Marques, Barbara, Martinsson, Tommy, Mazzocco, Katia, Morini, Martina, Muhlethaler-Mottet, Annick, Noguera, Rosa, Pierron, Gaelle, Rossing, Maria, Taschner-Mandl, Sabine, Van Roy, Nadine, Vicha, Ales, Chesler, Louis, Balwierz, Walentyna, Castel, Victoria, Elliott, Martin, Kogner, Per, Laureys, Genevieve, Luksch, Roberto, Malis, Josef, Popovic-Beck, Maja, Ash, Shifra, Delattre, Olivier, Valteau-Couanet, Dominique, Tweddle, Deborah A., Ladenstein, Ruth, and Schleiermacher, Gudrun

Abstract

PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n 5 330), ALK mutational profile (n 5 191), or both (n 5 571). RESULTS Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n 5 41] 28% [95% CI, 15 to 42]; no-ALKa [n 5 860] 51% [95% CI, 47 to 54], [P , .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (. 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P , .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n 5 19], 26% [95% CI, 10 to 47], clonal ALKm[n565] 33% [95% CI, 21 to 44], subclonal ALKm(n522) 48% [95% CI, 26 to 67], and no alteration [n 5 465], 51% [95% CI, 46 to 55], respectively; P 5 .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P , .001), ALKa (HR, 2.38; P 5 .004), and clonal ALKm (HR, 1.77; P 5 .001) were independent predictors of poor outcome. CONCLUSION Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integr

Published
2021

29. Long-Term Outcome and Role of Biology within Risk-Adapted Treatment Strategies: The Austrian Neuroblastoma Trial A-NB94

Author

Fiedler, Stefan, primary, Ambros, Inge M., additional, Glogova, Evgenia, additional, Benesch, Martin, additional, Urban, Christian, additional, Mayer, Marlene, additional, Ebetsberger-Dachs, Georg, additional, Bardi, Edit, additional, Jones, Neil, additional, Gamper, Agnes, additional, Meister, Bernhard, additional, Crazzolara, Roman, additional, Amann, Gabriele, additional, Dieckmann, Karin, additional, Horcher, Ernst, additional, Kerbl, Reinhold, additional, Brunner-Herglotz, Bettina, additional, Ziegler, Andrea, additional, Ambros, Peter F., additional, and Ladenstein, Ruth, additional

Published
2021
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30. Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group

Author

Ambros, Inge M., primary, Tonini, Gian-Paolo, additional, Pötschger, Ulrike, additional, Gross, Nicole, additional, Mosseri, Véronique, additional, Beiske, Klaus, additional, Berbegall, Ana P., additional, Bénard, Jean, additional, Bown, Nick, additional, Caron, Huib, additional, Combaret, Valérie, additional, Couturier, Jerome, additional, Defferrari, Raffaella, additional, Delattre, Olivier, additional, Jeison, Marta, additional, Kogner, Per, additional, Lunec, John, additional, Marques, Barbara, additional, Martinsson, Tommy, additional, Mazzocco, Katia, additional, Noguera, Rosa, additional, Schleiermacher, Gudrun, additional, Valent, Alexander, additional, Van Roy, Nadine, additional, Villamon, Eva, additional, Janousek, Dasa, additional, Pribill, Ingrid, additional, Glogova, Evgenia, additional, Attiyeh, Edward F., additional, Hogarty, Michael D., additional, Monclair, Tom F., additional, Holmes, Keith, additional, Valteau-Couanet, Dominique, additional, Castel, Victoria, additional, Tweddle, Deborah A., additional, Park, Julie R., additional, Cohn, Sue, additional, Ladenstein, Ruth, additional, Beck-Popovic, Maja, additional, De Bernardi, Bruno, additional, Michon, Jean, additional, Pearson, Andrew D. J., additional, and Ambros, Peter F., additional

Published
2020
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31. Single-cell landscape of bone marrow metastases in human neuroblastoma unraveled by deep multiplex imaging

Author

Lazic, Daria, primary, Kromp, Florian, additional, Kirr, Michael, additional, Mivalt, Filip, additional, Rifatbegovic, Fikret, additional, Halbritter, Florian, additional, Bernkopf, Marie, additional, Bileck, Andrea, additional, Ussowicz, Marek, additional, Ambros, Inge M, additional, Ambros, Peter F, additional, Gerner, Christopher, additional, Ladenstein, Ruth, additional, Ostalecki, Christian, additional, and Taschner-Mandl, Sabine, additional

Published
2020
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32. Risk factors in the HR-NBL-1/SIOPEN study in patients receiving dinutuximab beta (DB) based immunotherapy.

Author

Ladenstein, Ruth Lydia, primary, Poetschger, Ulrike, additional, Valteau-Couanet, Dominique, additional, Gray, Juliet, additional, Luksch, Roberto, additional, Balwierz, Walentyna, additional, Castel, Victoria, additional, Ash, Shifra, additional, Beck Popovic, Maja, additional, Laureys, Genevieve, additional, Chan, Godfrey Chi-Fung, additional, Ruud, Ellen, additional, Vettenranta, Kim, additional, Owens, Cormac, additional, Schroeder, Henrik, additional, Ambros, Peter F, additional, Sarnacki, Sabine, additional, Boterberg, Tom, additional, and Lode, Holger N., additional

Published
2020
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33. Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

Author

Weiss, Tamara, primary, Taschner-Mandl, Sabine, additional, Bileck, Andrea, additional, Rifatbegovic, Fikret, additional, Sorger, Helena, additional, Kauer, Max, additional, Frech, Christian, additional, Windhager, Reinhard, additional, Gerner, Christopher, additional, Ambros, Peter F., additional, and Ambros, Inge M, additional

Published
2020
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34. Genetic alterations of ALK in high-risk neuroblastoma patients. A SIOPEN study

Author

Bellini, Angela, Bernard, Virginie, Ambros, Inge, Ambros, Peter F., de Preter, Katleen, Combaret, Valérie, Beiske, Klaus, Jeison, Marta, Marques, Barbara, Morini, Martina, Mazzocco, Katia, Defferrari, Raffaella, Betts, David, Martinsson, Tommy, Mühlethaler-Mottet, Annick, Noguera, Rosa, Font de Mora, Jaime, Vicha, Ales, Ladenstein, Ruth, Valteau-Couanet, Dominique, Rossing, Caroline Maria, Bown, Nick, Tweddle, Deborah, Avigad, Smadar, Lapouble, Eve, Chicard, Mathieu, Leprovost, Nada, Clement, Nathalie, Baulande, Sylvain, Pierron, Gaelle, Irene, Jimenez, Jaydutt, Bhalshankar, Delattre, Olivier, Michon, Jean, and Schleiermacher, Gudrun

Subjects
Neuroblastoma, Tumor Genomics, ALK, hemic and lymphatic diseases, SIOPEN, Doenças Genéticas
Abstract

Background: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through genomic amplification or activating point mutations. We studied ALK genetic alterations in high-risk NB patients to determine their frequency and prognostic impact. Methods: Diagnostic NB samples from 1039 patients enrolled in the SIOPEN-HR-NBL1 trial were studied to determine the ALK amplification status (copy number analysis; n=337), the ALK mutational profile (Sanger and/or NGS including deep sequencing, n=203) or both (n=499). The sensitivity of ALK mutated/ALK amplified or ALK wildtype NB cell lines ((CLB-GA (R1275Q), CLB-GE (F1174V; ALK-A), SKNBE-2C (ALK wt)) to simultaneous or consecutive combinations of ALK TKIs (crizotinib/lorlatinib) and/or chemotherapy (Etoposide and Doxorubicin) was then tested. Results: Genomic ALK amplifications were detected in 4.4% of cases (37/836); all but 2 showed MYCN amplification. ALK mutations were detected at a clonal level (>20% mutated allele fraction, MAF) in 9.8% of cases (69/702) (F1174 n=25, R1275 n=32, both F1174 and R1275 n=1, F1245 n=6, others n=5) and at a subclonal level (MAF 0.5-20%) in 3.7% of patients (22/586) (F1174 n=11, R1275 n=6, both F1174 and R1275 or F1174 and F1245 n=3, other n=2). A significantly poorer OS and EFS was observed in cases with clonal ALK mutations, versus all others (3-years OS 47% +/-6.4% versus 65% +/-2%, logrank, p< 0.0001) and in those with ALK amplifications, versus all others (3-years OS 31% +/-8.5% versus 66% +/- 1.9%; logrank, p18 months were not retained. The consecutive treatment of Doxorubicin followed by Lorlatinib had a synergistic effect in ALK mutated/amplified NB cell lines. Conclusion: Genetic alterations of ALK (clonal mutations, amplifications) in high-risk NB patients are associated with poorer survival. Further preclinical data are required to determine optimal treatment modalities for integration of TKI in upfront treatment strategies of HR NB patients with ALK alterations. N/A

Published
2019

35. Frequency and Prognostic Impact of Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

Author

Bellini, Angela, Pötschger, Ulrike, Bernard, Virginie, Lapouble, Eve, Baulande, Sylvain, Ambros, Peter F, Auger, Nathalie, Beiske, Klaus, Bernkopf, Marie, Betts, David R, Bhalshankar, Jaydutt, Bown, Nick, de Preter, Katleen, Clément, Nathalie, Combaret, Valérie, Font de Mora, Jaime, George, Sally L, Jiménez, Irene, Jeison, Marta, and Marques, Barbara

Published
2021
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37. DeepSNP: An End-to-End Deep Neural Network with Attention-Based Localization for Breakpoint Detection in Single-Nucleotide Polymorphism Array Genomic Data

Author

Eghbal-Zadeh, Hamid, primary, Fischer, Lukas, additional, Popitsch, Niko, additional, Kromp, Florian, additional, Taschner-Mandl, Sabine, additional, Gerber, Teresa, additional, Bozsaky, Eva, additional, Ambros, Peter F., additional, Ambros, Inge M., additional, Widmer, Gerhard, additional, and Moser, Bernhard A., additional

Published
2019
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38. Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line high-risk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial.

Author

Ladenstein, Ruth Lydia, primary, Poetschger, Ulrike, additional, Valteau-Couanet, Dominique, additional, Gray, Juliet, additional, Luksch, Roberto, additional, Balwierz, Walentyna, additional, Castel, Victoria, additional, Ash, Shifra, additional, Beck Popovic, Maja, additional, Laureys, Genevieve, additional, Chan, Godfrey Chi Fung, additional, Ruud, Ellen, additional, Vettenranta, Kim, additional, Owens, Cormac, additional, Schroeder, Henrik, additional, Loibner, Hans, additional, Ambros, Peter F, additional, Sarnacki, Sabine, additional, Boterberg, Tom, additional, and Lode, Holger N., additional

Published
2019
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40. Abstract A17: Metronomic topotecan causes MYCN inactivation and impedes tumor growth selectively in MYCN-amplified neuroblastoma cells in vitro and in vivo by therapy-induced senescence

Author

Taschner-Mandl, Sabine, primary, Gerber, Teresa, additional, Schwarz, Magdalena, additional, Blaha, Johanna, additional, Kauer, Maximilian, additional, Kromp, Florian, additional, Frank, Nelli, additional, Rifatbegovic, Fikret, additional, Weiss, Tamara, additional, Ladenstein, Ruth, additional, Hohenegger, Martin, additional, Ambros, Inge M., additional, and Ambros, Peter F., additional

Published
2018
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41. Deep SNP: An End-to-end Deep Neural Network with Attention-based Localization for Break-point Detection in SNP Array Genomic data

Author

Eghbal-zadeh, Hamid, primary, Fischer, Lukas, additional, Popitsch, Niko, additional, Kromp, Florian, additional, Taschner-Mandl, Sabine, additional, Koutini, Khaled, additional, Gerber, Teresa, additional, Bozsaky, Eva, additional, Ambros, Peter F., additional, Ambros, Inge M., additional, Widmer, Gerhard, additional, and Moser, Bernhard A., additional

Published
2018
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42. Immunotherapy with anti-GD2 antibody ch14.18/CHO±IL2 within the HR-NBL1/SIOPEN trial to improve outcome of high-risk neuroblastoma patients compared to historical controls.

Author

Ladenstein, Ruth Lydia, primary, Poetschger, Ulrike, additional, Valteau Couanet, Dominique, additional, Gray, Juliet, additional, Luksch, Roberto, additional, Castel, Victoria, additional, Ash, Shifra, additional, Laureys, Genevieve, additional, Owens, Cormac, additional, Trahair, Toby, additional, Chan, Godfrey Chi Fung, additional, Ruud, Ellen, additional, Schroeder, Henrik, additional, Beck Popovic, Maja, additional, Loibner, Hans, additional, Schreier, Guenter, additional, Ambros, Peter F, additional, Sarnacki, Sabine, additional, Boterberg, Tom, additional, and Lode, Holger N., additional

Published
2018
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43. Risk prediction based on post induction bone marrow response and genomic profile: A new way to stratify stage M neuroblastoma patients?

Author

Fiedler, Stefan, primary, Ladenstein, Ruth Lydia, additional, Poetschger, Ulrike, additional, Abbasi, Reza, additional, Vicha, Ales, additional, Ash, Shifra, additional, Garaventa, Alberto, additional, Chan, Godfrey Chi Fung, additional, Balwierz, Walentyna, additional, Ussowicz, Marek, additional, Tweddle, Deborah, additional, Schleiermacher, Gudrun, additional, Mann, Georg, additional, Gabriel, Alem, additional, Jeison, Marta, additional, Klijanienko, Jerzy, additional, Morini, Martina, additional, Valteau Couanet, Dominique, additional, Ambros, Inge M, additional, and Ambros, Peter F, additional

Published
2018
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44. The randomised induction for high-risk neuroblastoma comparing COJEC and N5-MSKCC regimens: Early results from the HR-NBL1.5/SIOPEN trial.

Author

Garaventa, Alberto, primary, Poetschger, Ulrike, additional, Valteau-Couanet, Dominique, additional, Castel, Victoria, additional, Elliott, Martin, additional, Ash, Shifra, additional, Chan, Godfrey Chi-Fung, additional, Laureys, Genevieve, additional, Beck Popovic, Maja, additional, Vettenranta, Kim, additional, Balwierz, Walentyna, additional, Schroeder, Henrik, additional, Owens, Cormac, additional, Cesen, Maja, additional, Papadakis, Vassilios, additional, Trahair, Toby, additional, Luksch, Roberto, additional, Schleiermacher, Gudrun, additional, Ambros, Peter F, additional, and Ladenstein, Ruth Lydia, additional

Published
2018
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45. Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients

Author

Depuydt, Pauline, primary, Boeva, Valentina, additional, Hocking, Toby D, additional, Cannoodt, Robrecht, additional, Ambros, Inge M, additional, Ambros, Peter F, additional, Asgharzadeh, Shahab, additional, Attiyeh, Edward F, additional, Combaret, Valérie, additional, Defferrari, Raffaella, additional, Fischer, Matthias, additional, Hero, Barbara, additional, Hogarty, Michael D, additional, Irwin, Meredith S, additional, Koster, Jan, additional, Kreissman, Susan, additional, Ladenstein, Ruth, additional, Lapouble, Eve, additional, Laureys, Geneviève, additional, London, Wendy B, additional, Mazzocco, Katia, additional, Nakagawara, Akira, additional, Noguera, Rosa, additional, Ohira, Miki, additional, Park, Julie R, additional, Pötschger, Ulrike, additional, Theissen, Jessica, additional, Tonini, Gian Paolo, additional, Valteau-Couanet, Dominique, additional, Varesio, Luigi, additional, Versteeg, Rogier, additional, Speleman, Frank, additional, Maris, John M, additional, Schleiermacher, Gudrun, additional, and De Preter, Katleen, additional

Published
2018
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46. Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients

Author

Depuydt, Pauline, Boeva, Valentina, Hocking, Toby D., Cannoodt, Robrecht, Ambros, Inge M., Ambros, Peter F., Asgharzadeh, Shahab, Attiyeh, Edward F., Combaret, Valerie, Defferrari, Raffaella, Fischer, Matthias, Hero, Barbara, Hogarty, Michael D., Irwin, Meredith S., Koster, Jan, Kreissman, Susan, Ladenstein, Ruth, Lapouble, Eve, Laureys, Genevieve, London, Wendy B., Mazzocco, Katia, Nakagawara, Akira, Noguera, Rosa, Ohira, Miki, Park, Julie R., Poetschger, Ulrike, Theissen, Jessica, Tonini, Gian Paolo, Valteau-Couanet, Dominique, Varesio, Luigi, Versteeg, Rogier, Speleman, Frank, Maris, John M., Schleiermacher, Gudrun, De Preter, Katleen, Depuydt, Pauline, Boeva, Valentina, Hocking, Toby D., Cannoodt, Robrecht, Ambros, Inge M., Ambros, Peter F., Asgharzadeh, Shahab, Attiyeh, Edward F., Combaret, Valerie, Defferrari, Raffaella, Fischer, Matthias, Hero, Barbara, Hogarty, Michael D., Irwin, Meredith S., Koster, Jan, Kreissman, Susan, Ladenstein, Ruth, Lapouble, Eve, Laureys, Genevieve, London, Wendy B., Mazzocco, Katia, Nakagawara, Akira, Noguera, Rosa, Ohira, Miki, Park, Julie R., Poetschger, Ulrike, Theissen, Jessica, Tonini, Gian Paolo, Valteau-Couanet, Dominique, Varesio, Luigi, Versteeg, Rogier, Speleman, Frank, Maris, John M., Schleiermacher, Gudrun, and De Preter, Katleen

Abstract

Background: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low-and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations. Methods: In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome. Results: In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were detected in 5.9% of patients and were associated with a 10-year survival probability of only 3.4% (95% confidence interval [CI] = 0.5% to 23.3%, two-sided P = .002). Amplifications of regions not encompassing the MYCN locus were detected in 18.1% of patients and were associated with a 10-year survival probability of only 5.8% (95% CI = 1.5% to 22.2%, two-sided P < .001). Conclusions: Using a unique large copy number data set of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes.

Published
2018

47. Tumor Touch Imprints as Source for Whole Genome Analysis of Neuroblastoma Tumors

Author

Brunner, Clemens, Brunner-Herglotz, Bettina, Ziegler, Andrea, Frech, Christian, Amann, Gabriele, Ladenstein, Ruth, Ambros, Inge M., and Ambros, Peter F.

Subjects
0301 basic medicine, Loss of Heterozygosity, lcsh:Medicine, Genome, Loss of heterozygosity, Chromosomal Disorders, Neuroblastoma, 0302 clinical medicine, Neoplasms, Basic Cancer Research, Medicine and Health Sciences, Blastomas, lcsh:Science, DNA extraction, In Situ Hybridization, Fluorescence, Oligonucleotide Array Sequence Analysis, Genetics, Multidisciplinary, Chromothripsis, Chromosome Biology, SNP array, tumor touch imprint TTI, whole genome, tumor genetics, FISH, neuroblastoma, pediatric tumor, Signal Processing, Computer-Assisted, Genomics, DNA, Neoplasm, Chromosomal Aberrations, Oncology, 030220 oncology & carcinogenesis, Epigenetics, SNP array, Research Article, medicine.medical_specialty, Computational biology, Biology, Polymorphism, Single Nucleotide, Chromosomes, 03 medical and health sciences, Genomic Imprinting, Extraction techniques, Cancer Genomics, Genomic Medicine, Molecular genetics, medicine, Biomarkers, Tumor, SNP, Humans, ATRX, Clinical Genetics, Chromosome Aberrations, Genome, Human, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, Computational Biology, Cell Biology, Genome Analysis, Research and analysis methods, 030104 developmental biology, Feasibility Studies, lcsh:Q, Developmental Biology
Abstract

INTRODUCTION: Tumor touch imprints (TTIs) are routinely used for the molecular diagnosis of neuroblastomas by interphase fluorescence in-situ hybridization (I-FISH). However, in order to facilitate a comprehensive, up-to-date molecular diagnosis of neuroblastomas and to identify new markers to refine risk and therapy stratification methods, whole genome approaches are needed. We examined the applicability of an ultra-high density SNP array platform that identifies copy number changes of varying sizes down to a few exons for the detection of genomic changes in tumor DNA extracted from TTIs. MATERIAL AND METHODS: DNAs were extracted from TTIs of 46 neuroblastoma and 4 other pediatric tumors. The DNAs were analyzed on the Cytoscan HD SNP array platform to evaluate numerical and structural genomic aberrations. The quality of the data obtained from TTIs was compared to that from randomly chosen fresh or fresh frozen solid tumors (n = 212) and I-FISH validation was performed. RESULTS: SNP array profiles were obtained from 48 (out of 50) TTI DNAs of which 47 showed genomic aberrations. The high marker density allowed for single gene analysis, e.g. loss of nine exons in the ATRX gene and the visualization of chromothripsis. Data quality was comparable to fresh or fresh frozen tumor SNP profiles. SNP array results were confirmed by I-FISH. CONCLUSION: TTIs are an excellent source for SNP array processing with the advantage of simple handling, distribution and storage of tumor tissue on glass slides. The minimal amount of tumor tissue needed to analyze whole genomes makes TTIs an economic surrogate source in the molecular diagnostic work up of tumor samples.

Published
2016

49. Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Author

Abbasi, M. Reza, primary, Rifatbegovic, Fikret, additional, Brunner, Clemens, additional, Mann, Georg, additional, Ziegler, Andrea, additional, Pötschger, Ulrike, additional, Crazzolara, Roman, additional, Ussowicz, Marek, additional, Benesch, Martin, additional, Ebetsberger-Dachs, Georg, additional, Chan, Godfrey C.F., additional, Jones, Neil, additional, Ladenstein, Ruth, additional, Ambros, Inge M., additional, and Ambros, Peter F., additional

Published
2017
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50. Identification of Patient Subgroups with Markedly Disparate Rates of MYCN Amplification in Neuroblastoma: A Report from the International Neuroblastoma Risk Group (INRG) Project

Author

Thompson, Daria, Vo, Kieuhoa T., London, Wendy B., Fischer, Matthias, Ambros, Peter F., Nakagawara, Akira, Brodeur, Garrett M., Matthay, Katherine K., and DuBois, Steven G.

Subjects
Chromosome Aberrations, Male, Oncogene Proteins, N-Myc Proto-Oncogene Protein, Age Factors, Gene Amplification, Infant, Loss of Heterozygosity, Nuclear Proteins, Prognosis, Article, Neuroblastoma, Logistic Models, Predictive Value of Tests, Humans, Female, Neoplasm Grading, Neoplasm Staging
Abstract

MYCN gene amplification (MNA) is a hallmark of aggressive neuroblastoma. This study was performed to determine univariate and multivariate predictors of tumor MNA.Data from the International Neuroblastoma Risk Group were analyzed for a subset of 7102 patients with known MYCN status. Chi-square testing and logistic regression were used to identify univariate and multivariate predictors of MYCN status. Recursive partitioning was used to identify groups of patients with maximal differences in rates of MNA.All clinical features (age ≥ 18 months, high ferritin levels, high lactate dehydrogenase [LDH] levels, International Neuroblastoma Staging System stage 4, and adrenal sites) and pathological/biological features (DNA index ≤ 1, high mitosis-karyorrhexis index [MKI], undifferentiated/poorly differentiated grade, unfavorable histology according to the International Neuroblastoma Pathology Classification, and segmental chromosomal aberrations [SCAs]) were significantly associated with MNA. LDH (odds ratio [OR], 8.4; P.001) and chromosomal 1p loss of heterozygosity (OR, 19.8; P.001) were the clinical and biological variables, respectively, most strongly associated with MNA. In logistic regression, all variables except chromosome 17q aberration and pooled SCAs were independently predictive of MNA. Recursive partitioning identified subgroups with disparate rates of MNA, including subgroups with 85.7% MNA (patients with high LDH levels who had poorly differentiated adrenal tumors with chromosome 1p deletion) and 0.6% MNA (localized tumors having hyperdiploidy and low MKIs and lacking chromosome 1p aberrations).MNA is strongly associated with other clinical and biological variables in neuroblastoma. Recursive partitioning has identified subgroups of neuroblastoma patients with highly disparate rates of MNA. These findings can be used to inform investigations of molecular mechanisms of MNA.

Published
2015

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