Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors

Michael C Frühwald; Martin Hasselblatt; Karolina Nemes; Susanne Bens; Mona Steinbügl; Pascal D Johann; Kornelius Kerl; Peter Hauser; Eduardo Quiroga; Palma Solano-Paez; Veronica Biassoni; Maria Joao Gil-da-Costa; Martha Perek-Polnik; Marianne van de Wetering; David Sumerauer; Jane Pears; Niklas Stabell; Stefan Holm; Heinz Hengartner; Nicolas U Gerber; Michael Grotzer; Joachim Boos; Martin Ebinger; Stefan Tippelt; Werner Paulus; Rhoikos Furtwängler; Pablo Hernáiz-Driever; Harald Reinhard; Stefan Rutkowski; Paul-Gerhardt Schlegel; Irene Schmid; Rolf-Dieter Kortmann; Beate Timmermann; Monika Warmuth-Metz; Uwe Kordes; Joachim Gerss; Karsten Nysom; Reinhard Schneppenheim; Reiner Siebert; Marcel Kool; Norbert Graf

doi:10.1093/neuonc/noz244

Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors

Michael C Frühwald, Martin Hasselblatt, Karolina Nemes, Susanne Bens, Mona Steinbügl, Pascal D Johann, Kornelius Kerl, Peter Hauser, Eduardo Quiroga, Palma Solano-Paez, Veronica Biassoni, Maria Joao Gil-da-Costa, Martha Perek-Polnik, Marianne van de Wetering, David Sumerauer, Jane Pears, Niklas Stabell, Stefan Holm, Heinz Hengartner, Nicolas U GerberMichael Grotzer, Joachim Boos, Martin Ebinger, Stefan Tippelt, Werner Paulus, Rhoikos Furtwängler, Pablo Hernáiz-Driever, Harald Reinhard, Stefan Rutkowski, Paul-Gerhardt Schlegel, Irene Schmid, Rolf-Dieter Kortmann, Beate Timmermann, Monika Warmuth-Metz, Uwe Kordes, Joachim Gerss, Karsten Nysom, Reinhard Schneppenheim, Reiner Siebert, Marcel Kool, Norbert Graf

Afdeling for Børn og Unge

Abstrakt

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.

Originalsprog	Engelsk
Tidsskrift	Neuro-Oncology
Vol/bind	22
Udgave nummer	7
Sider (fra-til)	1006-1017
Antal sider	12
ISSN	1522-8517
DOI	https://doi.org/10.1093/neuonc/noz244
Status	Udgivet - 7 jul. 2020

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10.1093/neuonc/noz244

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Frühwald, M. C., Hasselblatt, M., Nemes, K., Bens, S., Steinbügl, M., Johann, P. D., Kerl, K., Hauser, P., Quiroga, E., Solano-Paez, P., Biassoni, V., Gil-da-Costa, M. J., Perek-Polnik, M., van de Wetering, M., Sumerauer, D., Pears, J., Stabell, N., Holm, S., Hengartner, H., ... Graf, N. (2020). Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors. Neuro-Oncology, 22(7), 1006-1017. https://doi.org/10.1093/neuonc/noz244

Frühwald, MC, Hasselblatt, M, Nemes, K, Bens, S, Steinbügl, M, Johann, PD, Kerl, K, Hauser, P, Quiroga, E, Solano-Paez, P, Biassoni, V, Gil-da-Costa, MJ, Perek-Polnik, M, van de Wetering, M, Sumerauer, D, Pears, J, Stabell, N, Holm, S, Hengartner, H, Gerber, NU, Grotzer, M, Boos, J, Ebinger, M, Tippelt, S, Paulus, W, Furtwängler, R, Hernáiz-Driever, P, Reinhard, H, Rutkowski, S, Schlegel, P-G, Schmid, I, Kortmann, R-D, Timmermann, B, Warmuth-Metz, M, Kordes, U, Gerss, J, Nysom, K, Schneppenheim, R, Siebert, R, Kool, M & Graf, N 2020, 'Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors', Neuro-Oncology, bind 22, nr. 7, s. 1006-1017. https://doi.org/10.1093/neuonc/noz244

@article{a3270236b09644b6905bb3a5cef67677,

title = "Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors",

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.",

keywords = "Adolescent, Adult, Age Distribution, Child, DNA Methylation, Europe, Female, Humans, In Situ Hybridization, Fluorescence, Male, Rhabdoid Tumor/genetics, Risk Factors, Teratoma/genetics, Young Adult",

author = "Fr{\"u}hwald, {Michael C} and Martin Hasselblatt and Karolina Nemes and Susanne Bens and Mona Steinb{\"u}gl and Johann, {Pascal D} and Kornelius Kerl and Peter Hauser and Eduardo Quiroga and Palma Solano-Paez and Veronica Biassoni and Gil-da-Costa, {Maria Joao} and Martha Perek-Polnik and {van de Wetering}, Marianne and David Sumerauer and Jane Pears and Niklas Stabell and Stefan Holm and Heinz Hengartner and Gerber, {Nicolas U} and Michael Grotzer and Joachim Boos and Martin Ebinger and Stefan Tippelt and Werner Paulus and Rhoikos Furtw{\"a}ngler and Pablo Hern{\'a}iz-Driever and Harald Reinhard and Stefan Rutkowski and Paul-Gerhardt Schlegel and Irene Schmid and Rolf-Dieter Kortmann and Beate Timmermann and Monika Warmuth-Metz and Uwe Kordes and Joachim Gerss and Karsten Nysom and Reinhard Schneppenheim and Reiner Siebert and Marcel Kool and Norbert Graf",

note = "{\textcopyright} 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.",

year = "2020",

month = jul,

day = "7",

doi = "10.1093/neuonc/noz244",

language = "English",

volume = "22",

pages = "1006--1017",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "7",

}

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

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 -

Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors

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