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: ATRT; DNA methylation profiling; European Rhabdoid Tumor Registry; SMARCB1; prognosis.

Fig. 1

The ATRT cohort of the EU-RHAB registry. A total of 143 ATRTs were analyzed. In 130 cases, enough DNA was available for SMARCB1 mutation analyses. In 93 tumors (= 186 alleles), enough material was present for analyses by FISH; sequencing and MLPA germline information was obtained in 117 patients. A total of 84 samples could be subclassified by 450k DNA methylation arrays.

Fig. 2

(A) Five-year survival (OS) of 143 consecutive patients treated according to the EU-RHAB consensus therapy. The 5-year overall survival (5y-OS) of the EU-RHAB cohort of 143 patients with ATRT was 34.7 ± 4.5% while the 5-year event-free survival (5y-EFS) of the same cohort was 30.5 ± 4.2%. OS was defined as the time from diagnosis until death of any cause or last visit. EFS was defined as the time from diagnosis until first progression, relapse, death of any cause, or last contact. (B) Age <1 year at diagnosis as an independent negative prognostic factor. The 5-year OS was 45.3 ± 6% for patients diagnosed after age 1 and 16.7 ± 5.7% for those <1 year at diagnosis. (C) Patients of the ATRT-TYR group demonstrate superior outcome compared with those of the ATRT-SHH and ATRT-MYC groups. The 5-year OS was superior in patients of the ATRT-TYR subgroup (48.8 ± 10.2%) versus 19 ± 8.8% for ATRT-SHH and final level not reached for the ATRT-MYC DNA-methylation subgroup (36.4 ± 12.5%). (D) Patients of the ATRT-TYR DNA-methylation subgroup have a significantly better prognosis compared with those of the non-TYR group. The 5-year OS was superior in patients of the ATRT-TYR subgroup (48.8 ± 10.2%) compared with those of the non-TYR subgroup (23.5 ± 7.7%).

Fig. 3

The genetic heterogeneity of SMARCB1 mutations in ATRT. The spectrum of SMARCB1 mutations in ATRT DNA-methylation subgroups among 72 patients is presented. Each column represents a DNA methylation subgroup as defined by a DNA methylation classifier. The x-axis gives the percentage of mutations detected in alleles in each subgroup. Whole gene deletions were rather common, followed in frequency by exon deletions and nonsense single nucleotide variations.

Fig. 4

A combined clinical and genetic risk model for stratification in ATRT Kaplan–Meier analyses (A). Patients with the risk factors age < or ≥1 year and features of the ATRT-TYR or non-TYR DNA-methylation subgroups were analyzed for their 5-year OS. Three risk strata were delineated: high risk (<1 y + non-TYR; 5-y OS 0%), intermediate risk (<1 y + 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). Potential risk model for the stratification of ATRT. (B) Age at diagnosis (<1 y vs ≥1 y) and DNA methylation subgroup (non-TYR vs TYR) may predict the potential risk of patients affected by ATRT independently of any other clinical or known genetic factor.