Michael C Frühwald1, Martin Hasselblatt1, Karolina Nemes1,2, Susanne Bens3, Mona Steinbügl1, Pascal D Johann4,5, Kornelius Kerl6, Peter Hauser7, Eduardo Quiroga8, Palma Solano-Paez8, Veronica Biassoni9, Maria Joao Gil-da-Costa10, Martha Perek-Polnik11, Marianne van de Wetering12, David Sumerauer13, Jane Pears14, Niklas Stabell15, Stefan Holm16, Heinz Hengartner17, Nicolas U Gerber18, Michael Grotzer18, Joachim Boos6, Martin Ebinger19, Stefan Tippelt20, Werner Paulus21, Rhoikos Furtwängler22, Pablo Hernáiz-Driever23, Harald Reinhard24, Stefan Rutkowski25, Paul-Gerhardt Schlegel26, Irene Schmid27, Rolf-Dieter Kortmann28, Beate Timmermann29, Monika Warmuth-Metz30, Uwe Kordes25, Joachim Gerss31, Karsten Nysom1,2, Reinhard Schneppenheim25, Reiner Siebert3, Marcel Kool4, Norbert Graf4. 1. University Children's Hospital Augsburg, Swabian Children's Cancer Center, Augsburg, Germany. 2. Department of Pediatrics and Adolescent Medicine, Neuroscience Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 3. Institute of Human Genetics, University of Ulm & University Hospital of Ulm, Ulm, Germany. 4. Hopp Children's Cancer Center, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany. 5. Department of Pediatric Oncology, Hematology, and Immunology, University Hospital Heidelberg, Heidelberg, Germany. 6. Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany. 7. Second Department of Pediatrics, Semmelweis University, Budapest, Hungary. 8. Department of Pediatric Oncology, Hospital Infantil Virgen del Rocio, Sevilla, Spain. 9. Pediatric Oncology Unit, Fondazione IRCCS National Tumor Institute, Milan, Italy. 10. Pediatric Hematology and Oncology Division, University Hospital S João Alameda Hernani Monteiro, Porto, Portugal. 11. Department of Oncology, The Children's Memorial Health Institute, Warsaw, Poland. 12. Princess Maxima Centre for Pediatric Oncology, Utrecht, Netherlands. 13. Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic. 14. Department of Pediatric Haematology and Oncology Our Lady's Children's Hospital, Dublin, Ireland. 15. Pediatric Department, Oncology Unit, University Hospital of North Norway, Tromso, Norway. 16. Karolinska University Hospital, Stockholm, Sweden. 17. Ostschweizer Kinderspital, St Gallen, Switzerland. 18. University Children's Hospital, Zürich, Switzerland. 19. Department of General Pediatrics, Hematology, and Oncology, Children's University Hospital Tübingen, Tübingen, Germany. 20. Department of Pediatric Hematology/Oncology, Pediatrics III, University Hospital of Essen, Essen, Germany. 21. Institute of Neuropathology, University Hospital Münster, Münster, Germany. 22. Department of Pediatric Hematology and Oncology, University of Saarland, Homburg, Germany. 23. Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, corporate member of the Free University Berlin, Humboldt University Berlin, and Berlin Institute of Health, Berlin, Germany. 24. Pediatrics, Asklepios Kinderklinik Sankt Augustin, Sankt Augustin, Germany. 25. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 26. Department of Pediatric Hematology and Oncology, University of Würzburg, Würzburg, Germany. 27. Department of Pediatric Hematology and Oncology, Ludwig-Maximilian-University, Munich, Germany. 28. Department of Radio-oncology, University of Leipzig, Leipzig, Germany. 29. Particle Therapy Clinics at West German Proton Therapy, University Hospital Essen, Essen, Germany. 30. Department of Neuroradiology, University Hospital Würzburg, Würzburg, Germany. 31. Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany.
Abstract
BACKGROUND: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. METHODS: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors. RESULTS: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%). CONCLUSIONS: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.
BACKGROUND: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. METHODS: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors. RESULTS: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%). CONCLUSIONS: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.
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