Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

Summary

Background

Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours.

Methods

We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling.

Findings

Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13–57, and 20%, 6–34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7–61, and 9%, 0–21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04–3·85; p=0·038) and 3·98 (1·71–9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes.

Interpretation

An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.

Funding

C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Introduction

CNS rhabdoid tumours, also called atypical teratoid rhabdoid tumours, are highly malignant neoplasms arising in very young children, with a median age of 18–22 months at diagnosis, and, until recently, were thought to be fatal.¹ Although the overall prognosis of patients with these tumours remains poor, with most patients living for less than 1 year from diagnosis, recent application of intensified multimodal therapy with whole craniospinal irradiation2, 3, 4 or high-dose chemotherapy with stem-cell rescue1, 3, 5, 6, 7 has improved survival. However, treatment intensification, particularly use of neuroaxis radiation, is associated with substantial acute and life-long physiological and neurological sequelae in these patients. Remarkably, long-term survival has been reported in some children with atypical teratoid rhabdoid tumours treated without neuroaxis radiation.5, 6, 8 These findings draw attention to the substantial clinical heterogeneity of atypical teratoid rhabdoid tumours and the need to avoid radiation and its associated neurotoxicity, without compromising survival. The biological basis for clinical heterogeneity in atypical teratoid rhabdoid tumours remains to be elucidated; this gap in knowledge has impeded development of therapeutic models and prospective treatment models.

Atypical teratoid rhabdoid tumours have histological features and hallmark alterations associated with the SMARCB1 (INI1/hSNF5/BAF47) tumour suppressor locus on chromosome 22q11.23 that are also detected in rhabdoid tumours arising in other locations.9, 10 Up to 35% of patients with the CNS rhabdoid tumours have germline SMARCB1 alterations and the rhabdoid predisposition syndrome characterised by development of several rhabdoid tumours.11, 12, 13 The biological relation between atypical teratoid rhabdoid tumours and non-CNS rhabdoid tumours remains unclear; however, atypical teratoid rhabdoid tumours are thought to develop from SMARCB1 loss in restricted, undefined, neural precursors. SMARCB1 is a constitutive component of the ubiquitous SWI/SNF chromatin remodelling complex that has specific functions in neural development.¹⁴ Results of animal studies show that loss of Snf is sufficient for the development of rhabdoid tumours, but intrinsic rhabdoid brain tumours have not been shown in Snf5–/– mice.15, 16, 17 Although the findings of studies of small cohorts suggest molecular heterogeneity might underlie the clinical range of atypical teratoid rhabdoid tumours, cumulative genomic analyses including whole-exome sequencing studies have shown SMARCB1 loss as the only recurrent genetic event in atypical teratoid rhabdoid tumours.18, 19 Reconciling clinical heterogeneity with tumour biology has been challenging for atypical teratoid rhabdoid tumours because it is a rare disease and there are only a few biological and clinical studies, thus determinants of survival and therapeutic responses remain poorly defined for patients. Furthermore, previous studies have been done on small, mixed cohorts of CNS and non-CNS rhabdoid tumours, and perhaps have lacked the power needed to define the genetic and molecular ranges of atypical teratoid rhabdoid tumours. In this study, we did integrated molecular and clinicopathological analyses of atypical teratoid rhabdoid tumours to define clinically relevant molecular classes of these tumours.