TY - JOUR
T1 - Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors
AU - Michael, C. Frühwald
AU - Martin, Hasselblatt
AU - Karolina, Nemes
AU - Susanne, Bens
AU - Mona, Steinbügl
AU - Pascal, D. Johann
AU - Kornelius, Kerl
AU - Peter, Hauser
AU - Eduardo, Quiroga
AU - Palma, Solano Paez
AU - Veronica, Biassoni
AU - Da-Costa Maria, Joao Gil
AU - Martha, Perek Polnik
AU - Van De Marianne, Wetering
AU - David, Sumerauer
AU - Jane, Pears
AU - Niklas, Stabell
AU - Stefan, Holm
AU - Heinz, Hengartner
AU - Nicolas, U. Gerber
AU - Michael, Grotzer
AU - Joachim, Boos
AU - Martin, Ebinger
AU - Stefan, Tippelt
AU - Werner, Paulus
AU - Rhoikos, Furtwängler
AU - Pablo, Hernaíz Driever
AU - Harald, Reinhard
AU - Stefan, Rutkowski
AU - Paul-Gerhardt, Schlegel
AU - Irene, Schmid
AU - Rolf-Dieter, Kortmann
AU - Beate, Timmermann
AU - Monika, Warmuth Metz
AU - Uwe, Kordes
AU - Joachim, Gerss
AU - Karsten, Nysom
AU - Reinhard, Schneppenheim
AU - Reiner, Siebert
AU - Marcel, Kool
AU - Norbert, Graf
N1 - Publisher Copyright:
© 2020 Oxford University Press. All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85088206647&partnerID=8YFLogxK
U2 - 10.1093/neuonc/noz244
DO - 10.1093/neuonc/noz244
M3 - Article
C2 - 31883020
AN - SCOPUS:85088206647
SN - 1522-8517
VL - 22
SP - 1006
EP - 1017
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - 7
ER -