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Cell Rep. 2019 Nov 19;29(8):2338-2354.e7. doi: 10.1016/j.celrep.2019.10.013. Epub 2019 Nov 7.

Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration.

Author information

1
Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V7Z 1L3, Canada.
2
Hopp Children's Cancer Center, Heidelberg 69120, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany.
3
Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada.
4
Department of Molecular Genetics, DKFZ, Heidelberg 69120, Germany.
5
Center for Digital Health, Berlin Institute of Health and Charité-Universitätsmedizin Berlin, Berlin 10117, Germany; Heidelberg Center for Personalized Oncology, DKFZ, Heidelberg 69120, Germany.
6
Hopp Children's Cancer Center, Heidelberg 69120, Germany.
7
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
8
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
9
Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
10
Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V7Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
11
Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry; and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg 97074, Germany.
12
Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster 48149, Germany.
13
Institute of Neuropathology, University Hospital Muenster, Muenster 48149, Germany.
14
University Children's Hospital Augsburg, Swabian Children's Cancer Center, Augsburg 86156, Germany.
15
Department of Pathology and Laboratory Medicine, Lurie Children's Hospital, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL 60611, USA.
16
Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8P 3E6, Canada.
17
Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V7Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada. Electronic address: mmarra@bcgsc.ca.
18
Hopp Children's Cancer Center, Heidelberg 69120, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany. Electronic address: m.kool@kitz-heidelberg.de.

Abstract

Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.

KEYWORDS:

HOX dysregulation; Malignant rhabdoid tumor; SMARCB1; atypical teratoid rhabdoid tumor; cytotoxic T cell infiltration; genomic and epigenomic dysregulation; molecular subgroups; pediatric cancer; tumor-infiltrating immune cells

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