Age and DNA-methylation subgroup as potential independent risk factors for treatment stratification in children with Atypical Teratoid/Rhabdoid Tumors (ATRT).

Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with Atypical Teratoid Rhabdoid Tumors (ATRT). The European Rhabdoid Registry, EU-RHAB, recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses.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. FISH, MLPA and sequencing were employed for assessment of somatic and germline mutations in SMARCB1. Molecular subgroups (ATRT-SHH, -TYR and -MYC) were determined using DNA-methylation arrays resulting in profiles of 84 tumors.Median age at diagnosis of 67 girls and 76 boys was 29.5 months. 5-year overall survival (OS) and event-free survival (EFS) were 34.7±4.5% and 30.5±4.2%. 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 ATRT (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 year + non-TYR; 5-year OS = 0%), intermediate risk (<1 year + ATRT-TYR or ≥1 year + non-TYR; 5-year OS = 32.5±8.7%) and standard risk (≥1 year + ATRT-TYR, 5-year OS = 71.5±12.2%).Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.