Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors. Issue 7 (28th December 2019)

• Record Type: Journal Article
• Authors: Frühwald, Michael C; Hasselblatt, Martin; Nemes, Karolina; Bens, Susanne; Steinbügl, Mona; Johann, Pascal D; Kerl, Kornelius; Hauser, Peter; Quiroga, Eduardo; Solano-Paez, Palma; Biassoni, Veronica; Gil-da-Costa, Maria Joao; Perek-Polnik, Martha; van de Wetering, Marianne; Sumerauer, David; Pears, Jane; Stabell, Niklas; Holm, Stefan; Hengartner, Heinz; Gerber, Nicolas U; Grotzer, Michael; Boos, Joachim; Ebinger, Martin; Tippelt, Stefan; Paulus, Werner; Furtwängler, Rhoikos; Hernáiz-Driever, Pablo; Reinhard, Harald; Rutkowski, Stefan; Schlegel, Paul-Gerhardt; Schmid, Irene; Kortmann, Rolf-Dieter; Timmermann, Beate; Warmuth-Metz, Monika; Kordes, Uwe; Gerss, Joachim; Nysom, Karsten; Schneppenheim, Reinhard; Siebert, Reiner; Kool, Marcel; Graf, Norbert;
• Is Part Of: Neuro-oncology. Volume 22:Issue 7(2020)
• Page Start: 1006
• Page End: 1017
• Publication Date: 2019-12-28
• Subjects: ATRT -- DNA methylation profiling -- European Rhabdoid Tumor Registry -- prognosis -- SMARCB1; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz244
• Languages: English
• ISSNs: 1522-8517

Abstract

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.