Intra- and extra-cranial Malignant Rhabdoid Tumours share common location-independent clinical and molecular disease characteristics.

Y Grabovska; MA Finetti; MP Selby; EC Schwalbe; A Smith; S Crosier; JC Pickles; AR Fairchild; A Avery; P O'Hare; B Pizer; B Brennan; S Lowis; D Hargrave; J Anderson; TS Jacques; S Bailey; SC Clifford; D Williamson

doi:10.1055/s-0038-1645013

Klinische Pädiatrie, Inhaltsverzeichnis

Klin Padiatr 2018; 230(03): 172
DOI: 10.1055/s-0038-1645013

Top 5 Cell biology and mechanisms of disease

Georg Thieme Verlag KG Stuttgart · New York

Intra- and extra-cranial Malignant Rhabdoid Tumours share common location-independent clinical and molecular disease characteristics.

Autoren

Y Grabovska

¹Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
MA Finetti

¹Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
MP Selby

¹Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
EC Schwalbe

²Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK
A Smith

¹Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
S Crosier

¹Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
JC Pickles

³Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, UK

⁴Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
AR Fairchild

³Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, UK

⁴Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
A Avery

⁴Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
P O'Hare

⁵Department of Paediatric Oncology, Great Ormond Street Hospital NHS Trust, London, UK.
B Pizer

⁶Institute of Translational Medicine, University of Liverpool, Liverpool, UK
B Brennan

⁷Royal Manchester Children's Hospital and University of Manchester, Manchester, UK
S Lowis

⁸Royal Hospital for Children and Bristol Medical School, University of Bristol, UK
D Hargrave

³Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, UK

⁵Department of Paediatric Oncology, Great Ormond Street Hospital NHS Trust, London, UK.
J Anderson

³Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, UK
TS Jacques

³Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, UK

⁴Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
S Bailey

¹Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
SC Clifford

¹Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
D Williamson

¹Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

Abstract

Volltext

Atypical Teratoid/Rhabdoid Tumours (ATRT) are the CNS located members of a larger family of Malignant Rhabdoid Tumours (MRT); aggressive early childhood tumours characterised by biallelic inactivation of SMARCB1. ATRT and extra-cranial rhabdoid tumours (ECRT) are often treated as distinct entities therapeutically and in clinical/biological studies. We investigated to what extent this division is justified by the underlying molecular biology.

RNA-Seq and methylation profiling of primary MRT was performed on 56 clinico-pathologically annotated tumour profiles from UK cancer centres and combined with published MRT data (n = 394) in a meta-analysis. To characterise the common biological features of MRT regardless of location, differential expression, methylation, gene/pathway analyses were compared to other paediatric embryonal tumour expression (n = 1073) and methylation (n = 520) profiles (i.e. Medulloblastoma, Ewings Sarcoma, Rhabdomyosarcoma, Wilms tumour and Neuroblastoma).

Clustering all MRT together recapitulates the subgroups observed in ATRT alone; broadly overlapping with recently published 3 ATRT subgroup models. We further describe a putative expanded subgrouping model encompassing all MRT. While expression, methylation, genetic and clinico-pathological differences by anatomical site are observed these are not innate but rather differences between ATRT and ECRT may be explained by differences in the molecular subgroup membership.

We propose that anatomical site does not exclusively predetermine subgroup identity and that the overarching SMARCB1-dependent genetic, epigenetic and transcriptomic commonality is the “main event” in MRT tumorigenesis. Our findings demonstrate a need for common therapeutic approaches and targeting strategies across all MRTs, irrespective of location; these findings have important implications for clinical trial planning and future research studies.