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

C. Frühwald Michael, Hasselblatt Martin, Nemes Karolina, Bens Susanne, Steinbügl Mona, D. Johann Pascal, Kerl Kornelius, Hauser Peter, Quiroga Eduardo, Solano Paez Palma, Biassoni Veronica, Joao Gil Da-Costa Maria, Perek Polnik Martha, Wetering Van De Marianne, Sumerauer David, Pears Jane, Stabell Niklas, Holm Stefan, Hengartner Heinz, U. Gerber NicolasGrotzer Michael, Boos Joachim, Ebinger Martin, Tippelt Stefan, Paulus Werner, Furtwängler Rhoikos, Hernaíz 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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

72 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)1006-1017
Aantal pagina's12
Nummer van het tijdschrift7
StatusGepubliceerd - 1 jul. 2020


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