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

Abstract

<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 &amp;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 &amp;lt; 0.05). An adjusted multivariate model identified age &amp;lt;1 year and a non-TYR signature as independent negative predictors of OS: high risk (&amp;lt;1 y + non-TYR; 5-y OS = 0%), intermediate risk (&amp;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>

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

“…Frequencies of germline mutations was taken from Frühwald et al [12]. Frequencies of ATRT-SMARCA4 is estimated based on studies published by Johann et al [22] and Frühwald et al [12].…”

“…In the vast majority of MRTs, pathogenic variants (hereafter “mutations”) affect the SMARCB1 gene. In rare cases (about 0.5–2% of ATRT [ 12 , 22 ]), SMARCA4 is mutated instead [ 17 , 42 , 43 ]. Since these mutations result in loss of the respective protein, loss of staining for either SMARCB1 or SMARCA4 by immunohistochemistry is used as a diagnostic tool to ensure the diagnosis of an ATRT [ 30 ].…”

“…The subgroups differ in the expression of distinct genes, the activation of specific signaling pathways, and in clinical parameters. For instance, ATRT-TYR, especially when older than 12 months, have been associated with a slightly better prognosis compared to the other subgroups or younger patients [ 12 ]. In addition to the subgrouping of ATRTs, extra-cranial MRTs (eMRTs) can also be further divided into subgroups based on molecular characteristics [ 5 , 6 ].…”

Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy

“…Oncology Group ACNS0333 study, with some suggestion that ATRT-SHH benefit from high-dose chemotherapy approaches and ATRT-TYR benefit from radiotherapy [116,[118][119][120][121]. The EZH2 inhibitor tazemetostat is a rational approach to target the SWI/SNF complex and is being investigated in upcoming clinical trials; however, there is a paucity of early phase human data at the present time [122].…”

Novel Two MRT Cell Lines Established from Multiple Sites of a Synchronous MRT Patient

“…Pinto et al have performed DNA-methylation profiling on their metachronous RT cases and reported that the CNS tumor cells often show methylation profiles distinct from those in extra-CNS tumor cells of the same patient (23). Data obtained by means of DNA methylation profiling are expected to further contribute to new valuable insights for a more profound understanding of molecular mechanisms of ATRTs and extra-CNS MRTs (9).…”