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

Medientyp: E-Artikel
Titel: Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors
Beteiligte: Frühwald, Michael C; Hasselblatt, Martin; Nemes, Karolina; Bens, Susanne; Steinbügl, Mona; Johann, Pascal D; Kerl, Kornelius; Hauser, Peter; Quiroga, Eduardo; Solano-Paez, Palma; Biassoni, Veronica; Gil-da-Costa, Maria Joao; Perek-Polnik, Martha; van de Wetering, Marianne; Sumerauer, David; Pears, Jane; Stabell, Niklas; Holm, Stefan; Hengartner, Heinz; Gerber, Nicolas U; Grotzer, Michael; Boos, Joachim; Ebinger, Martin; Tippelt, Stefan; [...]
Erschienen: Oxford University Press (OUP), 2020
Erschienen in: Neuro-Oncology
Sprache: Englisch
DOI: 10.1093/neuonc/noz244
ISSN: 1522-8517; 1523-5866
Schlagwörter: Cancer Research ; Neurology (clinical) ; Oncology
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Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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 &lt;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 &lt; 0.05). An adjusted multivariate model identified age &lt;1 year and a non-TYR signature as independent negative predictors of OS: high risk (&lt;1 y + non-TYR; 5-y OS = 0%), intermediate risk (&lt;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%).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.</jats:p> </jats:sec>
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