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.

2nd Department of Pediatrics Semmelweis University Budapest Hungary

Department of General Pediatrics Hematology and Oncology Children's University Hospital Tübingen Tübingen Germany

Department of Neuroradiology University Hospital Würzburg Würzburg Germany

Department of Oncology The Children's Memorial Health Institute Warsaw Poland

Department of Pediatric Haematology and Oncology Our Lady's Children's Hospital Dublin Ireland

Department of Pediatric Hematology and Oncology Ludwig Maximilian University Munich Germany

Department of Pediatric Hematology and Oncology University Children's Hospital Münster Münster Germany

Department of Pediatric Hematology and Oncology University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Pediatric Hematology and Oncology University of Saarland Homburg Germany

Department of Pediatric Hematology and Oncology University of Würzburg Würzburg Germany

Department of Pediatric Hematology Oncology Pediatrics 3 University Hospital of Essen Essen Germany

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

Department of Pediatric Oncology Hematology and Immunology University Hospital Heidelberg Heidelberg Germany

Department of Pediatric Oncology Hospital Infantil Virgen del Rocio Sevilla Spain

Department of Pediatrics and Adolescent Medicine Neuroscience Center Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Radio oncology University of Leipzig Leipzig Germany

Hopp Children's Cancer Center German Cancer Research Center and German Cancer Consortium Heidelberg Germany

Institute of Biostatistics and Clinical Research University of Münster Münster Germany

Institute of Human Genetics University of Ulm and University Hospital of Ulm Ulm Germany

Institute of Neuropathology University Hospital Münster Münster Germany

Karolinska University Hospital Stockholm Sweden

Ostschweizer Kinderspital St Gallen Switzerland

Particle Therapy Clinics at West German Proton Therapy University Hospital Essen Essen Germany

Pediatric Department Oncology Unit University Hospital of North Norway Tromso Norway

Pediatric Hematology and Oncology Division University Hospital S João Alameda Hernani Monteiro Porto Portugal

Pediatric Oncology Unit Fondazione IRCCS National Tumor Institute Milan Italy

Pediatrics Asklepios Kinderklinik Sankt Augustin Sankt Augustin Germany

Princess Maxima Centre for Pediatric Oncology Utrecht Netherlands

University Children's Hospital Augsburg Swabian Children's Cancer Center Augsburg Germany

University Children's Hospital Zürich Switzerland

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Tazemetostat in the therapy of pediatric INI1-negative malignant rhabdoid tumors

ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance