TY - JOUR
T1 - Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors
AU - Frühwald, Michael C
AU - Hasselblatt, Martin
AU - Nemes, Karolina
AU - Bens, Susanne
AU - Steinbügl, Mona
AU - Johann, Pascal D
AU - Kerl, Kornelius
AU - Hauser, Peter
AU - Quiroga, Eduardo
AU - Solano-Paez, Palma
AU - Biassoni, Veronica
AU - Gil-da-Costa, Maria Joao
AU - Perek-Polnik, Martha
AU - van de Wetering, Marianne
AU - Sumerauer, David
AU - Pears, Jane
AU - Stabell, Niklas
AU - Holm, Stefan
AU - Hengartner, Heinz
AU - Gerber, Nicolas U
AU - Grotzer, Michael
AU - Boos, Joachim
AU - Ebinger, Martin
AU - Tippelt, Stefan
AU - Paulus, Werner
AU - Furtwängler, Rhoikos
AU - Hernáiz-Driever, Pablo
AU - Reinhard, Harald
AU - Rutkowski, Stefan
AU - Schlegel, Paul-Gerhardt
AU - Schmid, Irene
AU - Kortmann, Rolf-Dieter
AU - Timmermann, Beate
AU - Warmuth-Metz, Monika
AU - Kordes, Uwe
AU - Gerss, Joachim
AU - Nysom, Karsten
AU - Schneppenheim, Reinhard
AU - Siebert, Reiner
AU - Kool, Marcel
AU - Graf, Norbert
N1 - © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PY - 2020/7/7
Y1 - 2020/7/7
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Age Distribution
KW - Child
KW - DNA Methylation
KW - Europe
KW - Female
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - Male
KW - Rhabdoid Tumor/genetics
KW - Risk Factors
KW - Teratoma/genetics
KW - Young Adult
U2 - 10.1093/neuonc/noz244
DO - 10.1093/neuonc/noz244
M3 - Journal article
C2 - 31883020
VL - 22
SP - 1006
EP - 1017
JO - Neuro-Oncology
JF - Neuro-Oncology
SN - 1522-8517
IS - 7
ER -