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

被引：89

作者：

Fruhwald, Michael C. ^{[1
]}

Hasselblatt, Martin ^{[2
]}

Nemes, Karolina ^{[1
]}

Bens, Susanne ^{[3
,4
]}

Steinbugl, Mona ^{[1
]}

Johann, Pascal D. ^{[5
,6
,7
]}

Kerl, Kornelius ^{[8
]}

Hauser, Peter ^{[9
]}

Quiroga, Eduardo ^{[10
]}

Solano-Paez, Palma ^{[10
]}

Biassoni, Veronica ^{[11
]}

Gil--Costa, Maria Joao ^{[12
]}

Perek-Polnik, Martha ^{[13
]}

van de Wetering, Marianne ^{[14
]}

Sumerauer, David ^{[15
]}

Pears, Jane ^{[16
]}

Stabell, Niklas ^{[17
]}

Holm, Stefan ^{[18
]}

Hengartner, Heinz ^{[19
]}

Gerber, Nicolas U. ^{[20
]}

Grotzer, Michael ^{[20
]}

Boos, Joachim ^{[8
]}

Ebinger, Martin ^{[21
]}

Tippelt, Stefan ^{[22
]}

Paulus, Werner ^{[2
]}

Furtwangler, Rhoikos ^{[23
]}

Hernaiz-Driever, Pablo ^{[24
,25
,26
,27
]}

Reinhard, Harald ^{[28
]}

Rutkowski, Stefan ^{[29
]}

Schlegel, Paul-Gerhardt ^{[30
]}

Schmid, Irene ^{[31
]}

Kortmann, Rolf-Dieter ^{[32
]}

Timmermann, Beate ^{[33
]}

Warmuth-Metz, Monika ^{[34
]}

Kordes, Uwe ^{[29
]}

Gerss, Joachim ^{[35
]}

Nysom, Karsten ^{[36
]}

Schneppenheim, Reinhard ^{[29
]}

Siebert, Reiner ^{[3
,4
]}

Kool, Marcel ^{[5
,6
]}

Graf, Norbert ^{[23
]}

机构：

[1] Univ Childrens Hosp Augsburg, Swabian Childrens Canc Ctr, Augsburg, Germany

[2] Univ Hosp Munster, Inst Neuropathol, Munster, Germany

[3] Univ Ulm, Inst Human Genet, Ulm, Germany

[4] Univ Hosp Ulm, Ulm, Germany

[5] Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany

[6] German Canc Consortium, Heidelberg, Germany

[7] Univ Hosp Heidelberg, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[8] Univ Childrens Hosp Munster, Dept Pediat Hematol & Oncol, Munster, Germany

[9] Semmelweis Univ, Dept Pediat 2, Budapest, Hungary

[10] Hosp Infantil Virgen Rocio, Dept Pediat Oncol, Seville, Spain

[11] Fdn IRCCS Natl Tumor Inst, Pediat Oncol Unit, Milan, Italy

[12] Univ Hosp S Joao Alameda Hernani Monteiro, Pediat Hematol & Oncol Div, Porto, Portugal

[13] Childrens Mem Hlth Inst, Dept Oncol, Warsaw, Poland

[14] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[15] Univ Hosp Motol, Dept Pediat Hematol & Oncol, Prague, Czech Republic

[16] Our Ladys Childrens Hosp, Dept Pediat Haematol & Oncol, Dublin, Ireland

[17] Univ Hosp North Norway, Pediat Dept, Oncol Unit, Tromso, Norway

[18] Karolinska Univ Hosp, Stockholm, Sweden

[19] Ostschweizer Sauglings & Kinderspital, St Gallen, Switzerland

[20] Univ Childrens Hosp, Zurich, Switzerland

[21] Childrens Univ Hosp Tubingen, Dept Gen Pediat Hematol & Oncol, Tubingen, Germany

[22] Univ Hosp Essen, Dept Pediat Hematol Oncol, Pediat 3, Essen, Germany

[23] Univ Saarland, Dept Pediat Hematol & Oncol, Homburg, Germany

[24] Charite Univ Med Berlin, Dept Pediat Oncol & Hematol, Berlin, Germany

[25] Free Univ Berlin, Berlin, Germany

[26] Humboldt Univ, Berlin, Germany

[27] Berlin Inst Hlth, Berlin, Germany

[28] Asklepios Kinderklin Sankt Augustin, Pediat, St Augustin, Germany

[29] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany

[30] Univ Wurzburg, Dept Pediat Hematol & Oncol, Wurzburg, Germany

[31] Ludwig Maximilians Univ Munchen, Dept Pediat Hematol & Oncol, Munich, Germany

[32] Univ Leipzig, Dept Radiooncol, Leipzig, Germany

[33] Univ Hosp Essen, Particle Therapy Clin West German Proton Therapy, Essen, Germany

[34] Univ Hosp Wurzburg, Dept Neuroradiol, Wurzburg, Germany

[35] Univ Munster, Inst Biostat & Clin Res, Munster, Germany

[36] Copenhagen Univ Hosp, Rigshosp, Neurosci Ctr, Dept Pediat & Adolescent Med, Copenhagen, Denmark

来源：

NEURO-ONCOLOGY | 2020年 / 22卷 / 07期

关键词：

ATRT; DNA methylation profiling; European Rhabdoid Tumor Registry; prognosis; SMARCB1; CENTRAL-NERVOUS-SYSTEM; TERATOID RHABDOID TUMORS; MOLECULAR SUBGROUPS; SURVIVAL; REGISTRY; FEATURES; THERAPY; ABSENCE; AT/RT;

D O I：

10.1093/neuonc/noz244

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1006 / 1017

页数：12

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